In untreated HIV-infected individuals, particularly those with advanced infection, lipid abnormalities are common (1,2). Abnormalities include a decrease in low density lipoprotein (LDL) cholesterol levels, while high density lipoprotein (HDL) cholesterol levels remain unchanged or decrease. The LDL particles in such individuals are mostly of a small dense LDL-β phenotype, which are more atherogenic than larger particles (2). In addition, plasma triglyceride levels are increased. Before the implementation of HAART, antiretroviral drugs such as zidovudine were shown to decrease plasma triglyceride levels (3). More recently, marked dyslipidemia with a different pattern has been observed in patients receiving PI-based HAART (4-6). In these patients, plasma levels of LDL cholesterol and total cholesterol were increased but there was no change in HDL cholesterol plasma levels. In addition, plasma triglyceride levels are elevated, in spite of enhanced HIV suppression. One cross-sectional study has revealed a higher than expected prevalence of atherosclerotic lesions in the carotid arteries of PI-treated patients when compared with patients naïve to treatment or treated with a regimen not containing PIs (7). However, another recently published study could not confirm this finding (8).
Concern exists that such alterations in lipid metabolism will be associated with an increase in the prevalence of cardiovascular disease (CVD) in HIV-infected individuals, particularly against the background of multiple conventional cardiovascular risk factors already present in HIV-infected populations in industrialized countries (9,10). At present, definitive epidemiological data confirming such an increased CVD risk are not available but studies in progress should clarify this situation.
Prospective epidemiological studies of non-HIV infected individuals, such as the Framingham Heart Study (11,12), the Prospective Cardiovascular Munster (PROCAM) Study (13,14), the Helsinki Heart Study (15) and the Lipid Research Clinics Prevalence Mortality Follow-up Study (16), have indicated that the risk of coronary artery disease is reduced by 2% to 5% for every 0.025 mmol/L increase in HDL cholesterol levels (17). An important mechanism underlying this protective effect is the role of HDL in the removal of excess cholesterol from peripheral tissues (reverse cholesterol transport) as reviewed by Hill and McQueen (18). Data from the PROCAM Study indicated that triglyceride plasma levels and HDL cholesterol plasma levels were important determinants of risk for cardiovascular disease irrespective of LDL cholesterol plasma levels (14).
This review summarizes the effects of nevirapine (NVP) on lipid metabolism in ARV-naïve patients and in ARV-treated patients who were switched to a PI-sparing regimen. The clinical implications of these findings are discussed.
NEVIRAPINE AND LIPID METABOLISM IN TREATMENT-NAÏVE PATIENTS
The Atlantic Study is an ongoing, open label, randomized, comparative study of 298 treatment-naïve HIV-infected patients with baseline plasma viral loads (pVLs) >500 copies/mL and CD4 cell counts >200 cells/mm3. The primary objective of this study was to evaluate the virological efficacy of three first-line ARV regimens (19). All patients received two nucleoside reverse transcriptase inhibitors (NRTIs): stavudine (d4T) and didanosine (ddI). In addition, they were randomized to receive NVP (400 mg once a day), lamivudine (3TC) (150 mg twice a day) or indinavir (IDV) (800 mg once every eight hours).
Week 48 data from the Atlantic Study indicated that virological control was similar in all three treatment arms (19). The proportion of patients achieving a plasma viral load of <50 copies/mL was 49% for IDV and NVP compared with 40% for 3TC (intention to treat analysis). All regimens were well tolerated. At week 96, the efficacy was equivalent in the NVP and IDV arms (55% and 44%, respectively, in the intention to treat analysis of data from <50 copies/mL assay) and inferior in the 3TC arm (28%) (p ≤ .001) (20).
Fat Redistribution and Metabolic Substudy (FRAMS); 24-week data
Patients were included in this substudy if they were still taking their assigned treatment after 24 weeks, and if blood samples (fasting not mandated) were available at baseline, week 6 and week 24 after the initiation of treatment (N = 114, 38% of the total study population) (17). Patients in the FRAMS substudy were representative of the overall Atlantic Study patients in terms of age, sex, risk factors for HIV infection, CDC class, baseline CD4 cell counts and pVLs. Two plasma samples were available for each patient at baseline, week 6 and week 24 of the study. The results are summarized in Figure 1.
Total cholesterol levels increased in all patients during the first six weeks of therapy. After this time, levels stabilized in NVP-treated patients but fell in those taking IDV- or 3TC-containing regimens. By week 24, total cholesterol plasma levels had increased by 18% in patients taking NVP/d4T/ddI (p < .001), by 7% in the IDV arm (p = .046) and by 1% in patients taking 3TC-containing regimens.
HDL cholesterol levels were similar in all three treatment groups at baseline. At 24 weeks, the HDL cholesterol plasma levels had increased by 49% from baseline in patients receiving the NVP-based regimen (p < .001 for comparison between baseline and week 24). Increases in HDL cholesterol plasma levels remained highly significant (all p < .001) after adjusting for baseline CD4 cell count, CD4 cell-count increase, baseline pVL, and pVL decrease (32%, 36%, 33%, and 34% increases from baseline values, respectively). Non-significant increases in HDL cholesterol of 16% were observed in the IDV and 3TC arms of the study. The difference between the NVP arm and the other two arms of the study in terms of HDL cholesterol changes was statistically significant (p < .001).
As a result of the increase in HDL cholesterol in the NVP-based treatment arm, the ratio between total cholesterol and HDL cholesterol significantly and very markedly decreased in the NVP treatment arm by 14% (p = .002). A decrease in this ratio is associated with a decreased incidence of coronary artery disease in non-HIV-infected individuals (21). A lesser reduction in this ratio was seen in patients who received the 3TC-containing regimen (9%, p = .029) but not in patients who received the IDV-containing regimen (0.9%, not significant).
LDL cholesterol levels increased in all three study arms by week six of the study. At this time point, LDL cholesterol levels had increased by 16% in NVP-treated patients compared with 11% in those taking IDV-containing regimens and 1% in those patients taking 3TC-containing regimens. During weeks six to 24 of the study, the LDL cholesterol levels stabilized in the NVP group, but fell slightly in patients taking IDV. LDL cholesterol levels returned to baseline in the 3TC-treated patients.
Apolipoprotein A1 is involved in reverse cholesterol transport by HDL (22). Transgenic overexpression of apo A1 in mice and rabbits inhibits progression of atherosclerosis. Using liver-directed gene transfer, others have also demonstrated that hepatic overexpression of the HDL proteins could increase HDL cholesterol levels and result in a rapid and marked regression of pre-existing atherosclerotic lesions in genetically modified mice (23,24). Increases in apo A1 were observed in all three treatment arms of the FRAMS study by week six (17). Levels continued to increase in patients taking NVP-containing regimens (19% increase compared with baseline by week 24) but stabilized in patients in the other two arms. The difference between the NVP and the 3TC arm was significant in this respect (p < .01).
Atlantic Study-Sustained Effect on Lipids at 96 Weeks
The in-depth 24 weeks FRAMS study showed that NVP is associated with increases in HDL cholesterol plasma levels, and a decrease in the ratio of total to HDL cholesterol, which is known to be associated with a reduced risk of CVD in other settings. An important question was whether this type of anti-atherogenic profile was sustained after a longer period of follow up. To answer this question, plasma samples were analyzed from 98 of the 198 Atlantic Study patients who were still taking their randomly assigned medications at week 96 and had plasma samples available at week 0 and week 96 (25). At 96 weeks, there was a 40% rise in HDL cholesterol plasma levels compared with baseline in patients in the NVP arm. These data suggest that the positive impact of NVP on the lipid profile is indeed sustained after 96 weeks of treatment.
EFFECT OF NEVIRAPINE ON LIPID METABOLISM IN PATIENTS SWITCHING FROM PROTEASE INHIBITORS
Two one-year studies have evaluated the effects on lipid metabolism of switching from a PI-containing HAART regimen to a PI-sparing regimen (26-28). In the one-year, multicentre, prospective, open-label study reported by Ruiz et al. (26), 108 patients with evident lipodystrophy and sustained viral suppression for more than 6 months when taking PI-based regimens were recruited (26). At week 48, a pVL of <400 copies/mL was maintained by 79% of patients who were switched to NVP and 77% of those who continued to take their PI-based regimen. Similar proportions of patients had pVLs of <50 copies/mL (74% and 72%, respectively). Absolute CD4 cell counts increased significantly in both groups compared with baseline values (112 and 76 cells/mm3). No significant changes in anthropometric or body shape measurements were observed after 48 weeks. Fasting total cholesterol and triglyceride levels decreased in the NVP-treated group compared with baseline values (p < .05) but no significant differences were seen between treatment groups at week 48.
In a substudy of the Ruiz et al. study, quantitative and qualitative changes in lipids and lipoproteins were assessed by nuclear magnetic resonance (NMR) spectroscopy after 24 weeks (27). Sixteen patients taking NVP-containing regimens and 18 patients continuing on their PI-containing treatment were included in this substudy. The patients had taken a PI-containing (mostly IDV) regimen for at least 9 months. Their pVLs had been <400 copies/mL for at least 6 months and all patients had evidence of clinical lipodystrophy. Patients were excluded if they had taken lipid lowering therapies for 4 months before enrolment. At baseline, the groups were well balanced in terms of age, gender, immune status and lipid profile. The majority of patients had an abnormal lipid profile: high total or LDL cholesterol plasma levels; low HDL cholesterol levels; high triglyceride plasma levels; or at least two of these lipid abnormalities. Only one patient in the group who switched to the NVP-containing regimen had very high total cholesterol plasma levels at baseline. The majority of patients were male and the average age was 35 years. The CD4 cell counts were high (approximately 600 cells/mm3) and all patients had pVLs <80 copies/mL at baseline.
After 24 weeks of follow up, there was a reduction from baseline in total cholesterol plasma levels (8.3%, p = .028), LDL cholesterol plasma levels (14%, p = .001), the number of circulating LDL particles (15%, p = .003) and very low density lipoprotein 1 (VLDL1) triglyceride plasma levels (44%, p = .032) in patients who were switched to a NVP-containing regimen. A significant rise in HDL cholesterol levels from baseline (20%, p = .002) and HDL particle size (3%, p < .001) was observed in these patients. There were no significant changes in the lipoprotein profiles of patients who continued to take PI-based regimens. The atherogenic index (total cholesterol, HDL cholesterol and C reactive protein levels) was significantly lower in the NVP-treated group (3.08) at 24 weeks compared with baseline (3.97, p = .001). There were no significant changes in this parameter in patients who continued to take PI-based regimens.
At 24 weeks, significantly more NVP-treated patients had one or more lipid parameters that had reverted to normal compared with the PI-treated patients (69% versus 23%, p < .05, 95% confidence interval 15%-76%). The greatest effects were seen in relation to HDL and LDL cholesterol plasma levels. HDL cholesterol reached recommended levels (>35 mg/dL) in 60% of the NVP-treated patients but in only 6% of the PI-treated group (p < .05, 95% confidence interval 21-86%). Fifty percent of the NVP-treated group achieved a normal LDL cholesterol level (defined as <200 mg/dL) compared with 14% in the PI-treated group (p < .05).
The improved lipid profiles (decreased total and LDL cholesterol and increased HDL cholesterol plasma levels, as well as increased sizes and a significant reduction in VLDL1 fraction) may be a result of halting the PI regimen, starting the new NVP-containing regimen or a combination of both changes. The decrease in VLDL1 may contribute to the reduction of LDL particles as VLDL1 stimulates the production of smaller LDL particles, which are more atherogenic (27). Given the observation of an increase in LDL cholesterol in the ARV-treatment naïve patients commencing first-line NVP-containing treatment in the FRAMS substudy, the decrease in LDL cholesterol levels in the switch patients is most likely due to the halting of PI treatment. In contrast, the very similar rise in HDL cholesterol levels in both studies is, most likely, the result of the inclusion of NVP in the treatment provided.
A second study, the Barcelona PI Switch Study, was a randomized, prospective, open-label study (28). Seventy-seven patients (pVL <80 copies/mL for at least 12 months; CD4 cell count of >300 cells/mm3 while taking a PI-containing regimen) were assigned to take their existing PI, NVP (200 mg twice a day) or efavirenz (EFV) (600 mg once a day). The NRTIs in the regimen were unchanged. Baseline characteristics were similar for all treatment groups.
At 12 months, 96% of patients in the NVP group had maintained a pVL of <80 copies/mL compared with 92% in the EFV- and PI-treated groups. Only five patients failed treatment (one taking NVP-based treatment, two taking EFV-based treatment and two taking PI-based regimens). There were significant increases in CD4 cell counts in all three groups at 12 months, compared with baseline (p ≤ .02). However, the differences between the groups in terms of CD4 cell increases or CD8 cell decreases were not significant.
NVP treatment was associated with an improvement in lipid profiles during 12 months of follow up. In the NVP-treated patients, there were significant decreases in total cholesterol plasma levels (p < .001), LDL cholesterol plasma levels (p < .03) and plasma triglyceride levels (p < .01) compared with baseline at three months and 12 months. There were no significant changes in these parameters in the PI- and EFV-treated patients. HDL cholesterol plasma levels and lipodystrophy symptoms did not alter in any of the treatment arms. The reasons why HDL cholesterol plasma levels did not alter in these NVP-treated patients are unknown at present.
First-line NVP containing treatment is associated with a favorable lipoprotein profile compared with first-line PI-containing treatment (17). Improvements observed in patients taking an NVP-based regimen included a decrease in the levels of atherogenic LDL particles and an increase in HDL cholesterol plasma levels. It is of note that statins (a group of widely prescribed cholesterol lowering drugs) have been reported to increase HDL cholesterol plasma levels by 7% (29). In contrast, NVP increased HDL levels by almost 50% from baseline in treatment-naïve patients (17). Improved lipid profiles were also observed in patients who switched from a PI-containing to a NVP-based regimen in one study but not in another (27,28).
Improving the lipid profiles of HIV-infected patients receiving long-term ARV treatment may be of benefit in reducing the risk factors that are associated with coronary artery disease. An association between dyslipidemic profiles, such as those observed in patients taking PI-containing treatment, and cardiovascular disease has been shown in non-HIV-infected populations. There is no evidence to suggest that HIV-infected patients will not be similarly affected. Further long-term prospective trials and cohort studies, however, are needed to explore the relationships fully between dyslipidemia, HIV infection and different commonly prescribed ARV therapy regimens. In addition, novel regimens that are expected to have a minimal adverse impact on lipid profiles (e.g., NVP, tenofovir and didanosine) are being studied.
In conclusion, first-line NVP treatment has been associated with a favorable lipoprotein profile. In addition, improved lipid profiles have been observed in patients who are switched from a PI-based regimen to a NVP-based regimen. Favorable lipid profiles may be of clinical benefit in reducing risk factors for coronary artery disease in HIV-1 infected patients who are receiving long-term ARV therapy.
1. Grunfeld C, Pang M, Doerrler W, et al. Lipids, lipoproteins, triglyceride clearance, and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. J Clin Endocrinol Metab
2. Feingold KR, Krauss RM, Pang M, et al. The hypertriglyceridemia of acquired immunodeficiency syndrome is associated with an increased prevalence of low density lipoprotein subclass pattern B. J Clin Endocrinol Metab
3. Mildvan D, Machado SG, Wilets I, Grossberg SE. Endogenous interferon and triglyceride concentrations to assess response to zidovudine in AIDS and advanced AIDS-related complex. Lancet
4. Carr A, Samaras K, Burton S, et al. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS
5. 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
6. 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. JAIDS
7. Maggi P, Serio G, Epifani G, et al. Premature lesions of the carotid vessels in HIV-1-infected patients treated with protease inhibitors. AIDS
8. Depairon M, Chessex S, Sudre P, et al. Premature atherosclerosis in HIV-infected individuals-focus on protease inhibitor therapy. AIDS
9. Galli M, Ridolfo AL, Gervasoni C. Cardiovascular disease risk factors in HIV-infected patients in the HAART era. Ann NY Acad Sci (USA)
10. Friis-Moller N, Reiss P, Kirk O, et al. Cardiovascular risk-factors in HIV patients-association with antiretroviral therapy. The D:A:D study [abstract 0 18]. Presented at the 8th European Conference on Clinical Aspects and treatment of HIV infection (ECCATH), Athens, Greece, 28-31 October 2001.
11. Abbott RD, Wilson PW, Kannel WB, Castelli WP. High density lipoprotein cholesterol, total cholesterol screening, and myocardial infarction. The Framingham Study. Arteriosclerosis
12. Wilson PW, Abbott RD, Castelli WP. High density lipoprotein cholesterol and mortality. The Framingham Heart Study. Arteriosclerosis
13. Assmann G, Schulte H. Relation of high-density lipoprotein cholesterol and triglycerides to incidence of atherosclerotic coronary artery disease (the PROCAM experience). Prospective Cardiovascular Munster study. Am J Cardiol
14. Assmann G. Pro and con: high-density lipoprotein, triglycerides, and other lipid subfractions are the future of lipid management. Am J Cardiol
15. Frick MH, Manninen V, Huttunen JK, et al. HDL-cholesterol as a risk factor in coronary heart disease. An update of the Helsinki Heart Study. Drugs
16. Jacobs, Jr, DR, Mebane IL, Bangdiwala SI, et al. High density lipoprotein cholesterol as a predictor of cardiovascular disease mortality in men and women: the follow-up study of the Lipid Research Clinics Prevalence Study. Am J Epidemiol
17. van der Valk M, Kastelein JJ, Murphy RL, et al. Nevirapine-containing antiretroviral therapy in HIV-1 infected patients results in an anti-atherogenic lipid profile. AIDS
18. Hill SA, McQueen MJ. Reverse cholesterol transport-a review of the process and its clinical implications. Clin Biochem
19. Squires K, Johnson V, Katlama C, et al. The Atlantic Study: a randomized, open-label trial comparing two protease inhibitors (PI)-sparing antiretroviral strategies versus a standard PI-containing regimen; final 48 week data. Presented at the 13th International AIDS Conference, Durban, South Africa, 9-14 July 2000.
20. van Leeuwen R. The Atlantic Study: a randomized, open-label trial comparing two protease inhibitor (PI)-sparing antiretroviral strategies versus a standard PI-containing regimen, 2 year follow-up data [abstract MoPeB3089]. Presented at the XIV International AIDS Conference, Barcelona, Spain, 7-12 July 2002.
21. Gordon T, Castelli WP, Hjortland MC, et al. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med
22. Stampfer MJ, Sacks FM, Salvini S, et al. A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction. N Engl J Med
23. Tangirala RK, Tsukamoto K, Chun SH, et al. Regression of atherosclerosis induced by liver-directed gene transfer of apolipoprotein A-I in mice. Circulation
24. Tsukamoto K, Tangirala R, Chun SH, et al. Rapid regression of atherosclerosis induced by liver-directed gene transfer of ApoE in ApoE-deficient mice. Arterioscler Thromb Vasc Biol
25. van der Valk M, Kastelein J, Murphy R, et al. Nevirapine containing potent antiretroviral therapy results in a sustained antiatherogenic plasma lipid profile: 96 week results from the Atlantic Study. Presented at the 8th European Conference on Clinical Aspects and treatment of HIV infection (ECCATH), Athens, Greece, 28-31 October 2001.
26. Ruiz L, Negredo E, Domingo P, et al. Antiretroviral treatment simplification with nevirapine in protease inhibitor-experienced patients with HIV-associated lipodystrophy: 1-year prospective follow-up of a multicenter, randomized, controlled study. JAIDS
27. Negredo E, Ribalta J, Paredes R, et al. Reversal of atherogenic lipoprotein profile in HIV-1 infected patients with lipodystrophy after replacing protease inhibitors by nevirapine. AIDS
28. Negredo E, Cruz L, Paredes R, et al. Virological, immunological, and clinical impact of switching from protease inhibitors to nevirapine or to efavirenz in patients with human immunodeficiency virus infection and long-lasting viral suppression. Clin Infect Dis
29. Jula A, Marniemi J, Huupponen R, et al. Effects of diet and simvastatin on serum lipids, insulin, and antioxidants in hypercholesterolemic men: a randomized controlled trial. JAMA
This publication has been made possible by an educational grant from Boehringer Ingelheim.