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Lipid Abnormalities Associated with ART May Be Different Than That Associated with Risk for Cardiovascular Disease in HIV negative Persons
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- In a German cohort of patients with hyperlipidemia associated with antiretroviral treatment (ART), levels of high density lipoprotein (HDL) and very low density lipoprotein (VLDL) cholesterol were higher than typically observed in patients with familial hyperlipidemia.
Based on these findings, the authors of a report in the January 24th issue of AIDS suggest that the risk for cardiovascular disease associated with ART may not be as great as previously assumed. They caution, however, that these findings need to be confirmed in prospective studies.
Dr. Stefan Mauss, of the Center for HIV and Hepatogastroenterology in Duesseldorf, and associates compared the lipid profiles of 187 HIV-infected patients with those of 10 individuals with familial combined hyperlipidemia and 14 with familial hypertriglyceridemia.
ART increased the levels of HDL-cholesterol compared with those in the 32 patients receiving no treatment. Among the 64 patients being treated with a protease inhibitor, total and LDL cholesterol and triglyceride levels were higher than those of patients not undergoing ART.
The 68 treated with a nonnucleoside reverse transcriptase inhibitor (NNRTI) exhibited higher total and LDL cholesterol levels as well as increased apolipoprotein A1. The 20 treated with nucleoside reverse transcriptase inhibitor (NRTI), apart from increased HDL levels, had profiles similar to their untreated counterparts. None of the patients was being treated with a combination of PI and NNRTI.
The authors measured the VLDL composition of 34 HIV-positive patients with elevated VLDL levels. The pattern of large VLDL particles with no increase in number resembled that of patients with familial hypertriglyceridemia, who have no or only a modestly increased risk of CVD.
In contrast, patients with familial combined hyperlipidemia, whose risk of CVD is elevated, have an increased number of small VLDL particles.
Dr. Mauss' group notes that their findings differ from those in other reports, where HIV-infected individuals exhibited lower HDL cholesterol. In their own cohort, HDL-cholesterol levels in patients with HIV infection and elevated VLDL were significantly higher than patients in either group of familial dyslipidemia.
"The large subgroup of HIV-positive patients taking antiretroviral treatment and with hypercholesterolemia caused by increased VLDL may have a lower cardiovascular risk than generally expected," they write. However, they do not rule out the possibility that these patients may have other important cardiovascular risk factors.
They advise that prospective studies examining these issues should include differentiated analysis of lipoprotein profiles and assessment of other cardiovascular risk factors.
AIDS 2003;17:189-194.
(Source: Reuters)
Differentiating hyperlipidaemia associated with antiretroviral therapy
Summary abstract:
Background: Hyperlipidaemia associated with antiretroviral treatment has led to concerns for an increased cardiovascular risk in
HIV-infected patients.
Objective: To assess this cardiovascular risk by comparing the lipoprotein pattern of antiretroviral-treated and untreated HIV-positive patients with patients with familial combined hyperlipidaemia (high cardiovascular risk) or familial hypertriglyceridaemia (low cardiovascular risk).
Methods: Fasting serum samples were drawn from consecutive patients with HIV infection or lipoprotein disorders. Total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, triglycerides,
apolipoprotein A1 and B were determined in serum. Very low density lipoprotein (VLDL) was prepared by ultracentrifugation and analysed for cholesterol, triglycerides and apolipoprotein B.
Results: Lipoprotein disorders were found in 114/187 HIV-positive patients (61%). Of these, according to the Fredrickson classification, 10% were type IIa (elevated LDL-cholesterol), 14% type IIb (elevated LDL- and VLDL-cholesterol) and 76% were type IV (elevated VLDL-cholesterol). VLDL composition was analysed in 34 HIV-positive patients with type IV hyperlipidaemia. The ratio of VLDL-triglycerides to VLDL-apolipoprotein B in these patients was 16.2 ± 6.0. This ratio was not different from 14 patients with famlial hypertriglyceridaemia (16.9 ± 6.0; P = 0.61), but differed substantially from 10 patients with familial combined hyperlipidaemia (6.8 ± 1.0; P < 0.0001).
Conclusions: In HIV-infected patients with high VLDL, large VLDL particles were found with no increase in number. This pattern resembles familial hypertriglyceridaemia. It is different from familial combined hyperlipidaemia, where an increase in number of small-sized VLDL particles occurs. Further research is needed to assess the contribution of VLDL-associated hypercholesterolaemia in those taking antiretroviral drugs to the cardiovascular risk profile of HIV-positive patients.
AIDS 2003; 17(2):189-194
Stefan Mauss a; Juergen Stechel b; Reinhard Willers c; Guenther Schmutz a; Florian Berger a; Werner O. Richter d
Excerpts from the published study results-
....In general, HDL-cholesterol, which is generally regarded as protective against cardiovascular events, is reported to be lower in HIV-infected individuals with or without antiretroviral treatment compared with the general population. However, in the present study, antiretroviral treatment was associated with an increase in HDL-cholesterol in HIV-positive patients. In direct comparison, HDL-cholesterol levels in HIV-positive patients with elevated VLDL were significantly higher than in patients with familial combined hyperlipidaemia or even those with familial hypertriglyceridaemia. These observations could suggest that the large subgroup of HIV-positive patients taking antiretroviral treatment and with hypercholesterolaemia caused by increased VLDL may have a lower cardiovascular risk than generally expected.
.. Protease inhibitor treatment resulted in elevated total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides compared with patients without antiretroviral treatment. Non-nucleoside reverse transcriptase inhibitor treatment was associated with higher total cholesterol, LDL-cholesterol, HDL-cholesterol and apolipoprotein A1. Nucleoside reverse transcriptase inhibitor treatment was associated only with increased HDL-cholesterol... In the present study, less than a third of the patients with high total cholesterol had an elevated LDL-cholesterol. This may be a result of genetically transmitted hypercholesterolaemia (as in the normal population) or an increased catabolism
of VLDL to LDL. An increase in LDL-cholesterol is associated with increased cardiovascular risk...
...familial combined hyperlipidaemia...is associated with high
cardiovascular risk through a secondary increase in LDL-cholesterol and apolipoprotein B, whereas familial hypertriglyceridaemia is asssociated with an only slightly increased cardiovascular risk and unchanged apolipoprotein B
and LDL-cholesterol levels...
Hyperlipidaemia is frequently associated with antiretroviral treatment and this has led to concerns about an increased cardiovascular risk in treated HIV-positive patients. The data on cardiovascular events in HIV-positive patients are anecdotal or retrospective and do not allow firm conclusions to be drawn regarding the influence of hyperlipidaemia associated with antiretroviral therapy on cardiovascular risk. High-resolution ultrasound studies assessing intima media thickness and the presence of atherosclerotic plaques as signs of premature atherosclerosis are conflicting. However, despite the lack of clear evidence, most clinicians assume that hyperlipidaemia associated with antiretroviral treatment does increase the cardiovascular risk, and treatment with lipid-lowering agents is common.
It has been shown that hypercholesterolaemia found in HIV-positive patients is frequently caused by the elevation of very low density lipoprotein (VLDL). Because of this, the proportion of hyperlipidaemia caused by VLDL in HIV-positive patients taking antiretroviral therapy is in excess of the proportion found in the general population. Two well-described genetically inherited lipid disorders that involve an increase in VLDL may serve as models to analyse
further the lipoprotein pattern in HIV-positive patients with elevated VLDL and to estimate their cardiovascular risk. Familial combined hyperlipidaemia is caused by overproduction of small VLDL particles in the liver, leading to a parallel increase in apolipoprotein B and is associated with increased cardiovascular risk. Familial hypertriglyceridaemia is characterized by production of normal numbers of large VLDL particles containing more triglycerides than normal. This results in normal apolipoprotein B levels and no or only modestly increased cardiovascular risk.
The Fredrickson classification of hyperlipoproteinaemias was used. Fredrickson type IIa is defined as LDL-cholesterol of > 160 mg/dl (4.13 mmol/l), type IIb as LDL-cholesterol > 160 mg/dl (4.13 mmol/l) and VLDL-cholesterol of > 35 mg/dl (0.90 mmol/l), and type IV as VLDL-cholesterol > 35 mg/dl (0.90 mmol/l) without an increase in LDL-cholesterol.
In the present study, lipoprotein patterns were analysed in HIV-positive patients with and without antiretroviral treatment, HIV-seronegative patients with familial combined hyperlipidaemia (high cardiovascular risk) or with familial hypertriglyceridaemia (low cardiovascular risk). In addition the size of VLDL particles were measured in a subgroup of HIV-positive patients who had Fredrickson type IV hyperlipidaemia and this was compared with that in those with the familial dyslipidaemias.
Fasting serum samples were drawn in the morning from 187 consecutive HIV-positive patients over a 4 week period in two private practices. The samples from 14 HIV-seronegative patients with familial hypertriglyceridaemia and 10
patients with combined familial hyperlipidaemia were analysed as controls.
Total cholesterol, low density lipoprotein (LDL)-cholesterol, high density lipoprotein (HDL)-cholesterol, triglycerides, apolipoprotein A1 and B were determined in serum. VLDL was analysed for cholesterol, triglyceride and apolipoprotein B. Age, sex, CD4 cell count, CD8 cell count, clinical stage of HIV infection [according to the Centers for Disease Control (CDC) classification 1993], HIV RNA, body mass index and antiretroviral substances were recorded and used as parameters for the multivariate analysis.
For a grouped analysis of the antiretroviral therapy regimen, patients were assigned to three antiretroviral treatment groups as follows: the protease inhibitor group, where the regimen included one or several protease inhibitors plus one or several nucleoside reverse transcriptase inhibitors; the non-nucleoside reverse transcriptase inhibitor group, when the regimen contained one non-nucleoside reverse transcriptase inhibitor plus one or several nucleoside reverse transcriptase inhibitors; the nucleoside reverse transcriptase inhibitor group, who were treated with nucleoside reverse transcriptase inhibitors only. Patients treated with a combination containing a protease inhibitor and a non-nucleoside reverse transcriptase inhibitor were excluded from the study.
Results
Of the 187 HIV-positive patients enrolled in the study, 32 patients (17%) were treatment-naive, 20 (11%) received nucleoside reverse transcriptase inhibitors only, 68 (36%) a regimen containing a non-nucleoside reverse transcriptase
inhibitor, 64 (34%) a protease inhibitor containing regimen. Patient on nucleoside reverse transcriptase inhibitors only showed no difference in the distribution of symptomatic HIV infection according to the CDC classification compared with patients without antiretroviral treatment. Compared with HIV-positive patients who were not taking antiretroviral therapy, patients taking HIV protease inhibitors had more frequently a history of an AIDS-defining event and patients treated with non- nucleoside reverse transcriptase inhibitors had more frequently a history of a non-AIDS defining HIV-associated clinical event.
Cd4 counts were 475-600, 475 on average in the PI group, 540 in the NRTI group, 600 in the NNRTI group, and 580 in the no ART group. Viral load was <50 on average in the PI, NNRTI, and ART groups and 38,000 in the no ART group. The NRTI group tended to use AZT, 3TC and abacavir more often and d4T and ddI less often. The PI group tended to use ritonavir and Kaletra more often followed by saquinavir and indinavir, and then nelfinavir and amprenavir less often.
Hypercholesterolaemia, defined as a fasting total cholesterol level of > 200 mg/dl (5.17 mmol/l), was found in 85/187 patients (45%). Elevated serum triglycerides of > 200 mg/dl (2.3 mmol/l) were found in 103/187 (55%) patients. Of the 114 HIV-positive patients with hyperlipidaemia, 11/114 (10%) were type IIa (elevated LDL-cholesterol), 16/114 (14%) type IIb (elevated
LDL- and VLDL-cholesterol) and 87/114 (76%) type IV (elevated VLDL-cholesterol). Eleven of the 187 patients had triglycerides > 800 mg/dl (9.2 mmol/l).
Protease inhibitor treatment resulted in elevated total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides compared with patients without antiretroviral treatment. Non-nucleoside reverse transcriptase inhibitor treatment was associated with higher total cholesterol, LDL-cholesterol, HDL-cholesterol and apolipoprotein A1. Nucleoside reverse transcriptase inhibitor treatment was associated only with increased HDL-cholesterol.
Protease inhibitor treatment resulted in elevated total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides compared with patients without antiretroviral treatment. Non-nucleoside reverse transcriptase inhibitor treatment was associated with higher total cholesterol, LDL-cholesterol, HDL-cholesterol and apolipoprotein A1. Nucleoside reverse transcriptase inhibitor treatment was associated only with increased HDL-cholesterol.
In a multivariate analysis, elevated total cholesterol was associated with age > 40 years (P = 0.004) and with treatment with ritonavir (P = 0.002), efavirenz (P = 0.007) or indinavir (P = 0.03). An elevated LDL-cholesterol was associated
with treatment with fortovase (P = 0.02), indinavir (P = 0.02) or efavirenz (P = 0.04). Higher apolipoprotein B levels were associated with higher age (P = 0.02) and treatment with lopinavir (P = 0.03). An increased HDL-cholesterol was
associated with female sex (P = 0.003) and treatment with didanosine (P = 0.01). Higher apolipoprotein A1 was associated with a higher CD4 cell count (P = 0.005) and showed a trend for treatment with efavirenz (P = 0.06).
Hypertriglyceridaemia was associated with stavudine and abacavir treatment in a univariate analysis, but no variable survived in the multivariate model.
HDL-cholesterol in HIV-positive patients without antiretroviral treatment is generally lower than in the normal population. However antiretroviral treatment of any kind increased the HDL-cholesterol. In addition,
compared with patients with familial combined hyperlipidaemia and familial hypertriglyceridaemia, HIV-positive patients had higher HDL- cholesterol levels.
Cardiovascular risk was assessed further by measuring the VLDL composition from 34 HIV-positive patients with type IV hyperlipidaemia (elevated VLDL-cholesterol). The size and the number of the VLDL particles was calculated from the ratio of VLDL-triglycerides to VLDL-apolipoprotein B in the VLDL fraction prepared by ultracetrifugation. Two different cohorts were used as controls. Patients with familial hypertriglyceridaemia show a normal number of large triglyceride-rich VLDL particles, resulting in a high ratio of VLDL-triglycerides to VLDL-apolipoprotein B. Patients with familial combined hyperlipidaemia, where the number of normally sized particles is increased, are characterized by a low ratio. In the HIV-positive patients, the ratio of VLDL-triglycerides to VLDL-apolipoprotein B was 16.2 ± 6.0 (range, 9.4-42.5). This ratio was not different from the ratio found in 14 patients with familial hypertriglyceridaemia, 16.9 ± 6.0 (range, 8.8-24.3; P = 0.61). In contrast, the ratio of VLDL-triglycerides to VLDL-apolipoprotein B in these two groups differed highly from the 10 patients with familial combined hyperlipidaemia, who had a ratio of 6.7 ± 1.0 (range, 5.3-8.5; P < 0.00001). The range of the individual measurements did not even show an overlap between familial combined hyperlipidaemia and the other two groups. In addition, patients with familial combined hyperlipidaemia showed increased serum apolipoprotein B compared with patients with HIV-associated hyperlipidaemia or familial hypertriglyceridaemia.
Discussion by authors
In accordance with previous reports, the present study showed higher cholesterol and lipid levels in association with antiretroviral therapy, particularly in patients treated with regimen containing a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor. In the multivariate analysis, some protease inhibitors and the non-nucleoside reverse transcriptase inhibitor efavirenz were associated with an increase in total cholesterol and LDL-cholesterol. Treatment with nucleoside reverse transcriptase inhibitors only seemed not to have a profound effect on the lipid profile. Interestingly, antiretroviral treatment was associated with an increase in HDL-cholesterol and, in those taking a non-nucleoside reverse transcriptase inhibitor, with increased apolipoprotein A1, which is associated with HDL-cholesterol. Such an effect has been reported for efavirenz and nevirapin as part of nucleoside reverse transcriptase inhibitor-based treatment.
Very high levels of triglycerides, which may present a significant risk for the development of acute pancreatitis, were observed in a considerable minority of this cohort and 6 of these 11 patients received ritonavir as part of their
antiretroviral regimen.
The most common cause for high total cholesterol in HIV-positive patients taking antiretroviral therapy in this and other studies was elevated VLDL. As the lipid content of VLDL is 80% triglycerides and 20% cholesterol, the increased
concentration of VLDL leads to an elevated total cholesterol. An interaction between sterol regulatory element-binding protein-1C, a key element in the regulation of lipogenesis, and antiretroviral drugs is one of the proposed mechanisms for this phenomenon. Additional factors may be HIV infection itself or a genetic predisposition.
In the present study, less than a third of the patients with high total cholesterol had an elevated LDL-cholesterol. This may be a result of genetically transmitted hypercholesterolaemia (as in the normal population) or an increased catabolism of VLDL to LDL. An increase in LDL-cholesterol is associated with increased cardiovascular risk. The situation with increased VLDL-cholesterol is more complex, as highlighted by the two genetically determined hyperlipidaemias discussed: familial combined hyperlipidaemia and familial hypertriglyceridaemia. The former is associated with high cardiovascular risk through a secondary increase in LDL-cholesterol and apolipoprotein B, whereas familial hypertriglyceridaemia is asssociated with an only slightly increased cardiovascular risk and unchanged apolipoprotein B and LDL-cholesterol levels. The pattern of dyslipidaemia in HIV-positive patients taking antiretroviral therapy and with Fredrickson type IV dyslipoproteinaemia resembles familial hypertriglyceridaemia rather than familial combined hyperlipidaemia. The analysis of VLDL particle size indicated that the particles in HIV-positive patients were large, similar to those in patients with familial hypertriglyceridaemia. No overlap of particle size was found between the 34 HIV-positive patients and the patients with familial combined hyperlipidaemia.
In general, HDL-cholesterol, which is generally regarded as protective against cardiovascular events, is reported to be lower in HIV-infected individuals with or without antiretroviral treatment compared with the general population. However, in the present study, antiretroviral treatment was associated with an increase in HDL-cholesterol in HIV-positive patients. In direct comparison, HDL-cholesterol levels in HIV-positive patients with elevated VLDL were significantly higher than in patients with familial combined hyperlipidaemia or even those with familial hypertriglyceridaemia.
These observations could suggest that the large subgroup of HIV-positive patients taking antiretroviral treatment and with hypercholesterolaemia caused by increased VLDL may have a lower cardiovascular risk than generally expected. A differentiated analysis of the lipoprotein pattern should be included in prospective studies assessing the cardiovascular risk of HIV-positive patients to test this hypothesis. However, the contribution of other important cardiovascular risk factors frequently found in HIV-positive patients taking antiretroviral treatment, such as insulin resistance, must also be considered in prospective studies.
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