Women had higher mean TC, LDL, and HDL values, and lower triglyceride values compared with men in adjusted analyses (Table 4). African-American individuals had higher mean TC, LDL, triglyceride, and non-HDL values, and lower HDL values compared with white individuals. Older age was associated with higher TC, LDL, HDL, triglyceride, and non-HDL values. HCV was associated with lower TC, LDL, triglyceride, and non-HDL values (Table 4). CD4+ nadir was associated with higher TC levels. There were no significant associations between patients with HBV, prior nonpotent ART (NRTIs), or opportunistic infections and lipid levels.
Mean lipid levels were higher at all follow-up time periods compared with baseline. In general, lipid levels increased most rapidly during the first 2 months and then either reached a plateau or continued to increase much more slowly (Table 5).
Patients receiving tenofovir/lamivudine (or tenofovir/emtricitabine) had lower lipid levels than other NRTI pairs. Specifically, TC levels were significantly higher among patients who received any other NRTI pair compared with tenofovir/lamivudine (+10–22 mg/dl, P values <0.001–0.002) (Table 6). Mean triglyceride values were higher among patients receiving any other NRTI pair compared with tenofovir/lamivudine in adjusted analyses; however, most of these increases did not reach statistical significance. Compared with patients on tenofovir/lamivudine, receiving stavudine/lamivudine, didanosine/lamivudine or zidovudine/lamivudine was associated with higher non-HDL levels. A similar effect cannot be ruled out for other NRTI pairs although they did not reach statistical significance. In comparison to tenofovir/lamivudine, patients receiving any other NRTI pair had higher HDL levels in adjusted analyses (+3–11 mg/dl, P values <0.001–0.02) (Table 6).
Regimens containing didanosine/lamivudine had the greatest impact on LDL levels (+12 mg/dl, P = 0.03). Didanosine/stavudine was associated with similarly higher LDL levels as didanosine/lamivudine (+14 mg/dl), although this did not reach statistical significance in the main model, it was significant in sensitivity analyses (see below).
Triglyceride analyses were repeated using natural log-transformed values in order to address the skewed distribution. In addition to the findings in the main model (Table 6), elevated triglyceride values were also associated with zidovudine/lamivudine (P = 0.01) compared with tenofovir/lamivudine.
In addition, we conducted sensitivity analyses that included change in BMI among 823 patients with change in BMI available at 6 months (±3 months). Change in BMI was associated with higher TC (1.9 mg/dl per kg/m2, P = 0.02), LDL (1.5 mg/dl per kg/m2, P = 0.006), triglycerides (5.7 mg/dl per kg/m2, P = 0.03), and non-HDL values (2.1 mg/dl per kg/m2, P = 0.009) but not HDL levels. Associations between antiretroviral medications and change in lipid levels were virtually unchanged in models that also adjusted for change in BMI over 6 months compared with the main models except didanosine/stavudine use was also associated with increased LDL (+14 mg/dl, 95% CI 1–28, P = 0.04), triglyceride (+128 mg/dl, 95% CI 13–244, P = 0.03), and non-HDL values (+29 mg/dl, 95% CI 10–49, P = 0.003).
We examined the impact of statins and other lipid-lowering medications on our findings in sensitivity analyses among patients from three sites with information regarding these medications. Findings were similar to the main models after also adjusting for statins and other lipid-lowering medications.
Findings from this large longitudinal study of HIV-infected patients in routine care demonstrated that patients whose initial regimen contained tenofovir/lamivudine (or tenofovir/emtricitabine) had the smallest increase in lipid levels for all lipid outcomes including not only pro-atherogenic lipids, but also HDL in adjusted analyses. Didanosine/lamivudine was associated with greater increases in LDL values. This study demonstrated the importance of comparing antiretroviral medications within classes and not just focusing on class effects. This study also demonstrated that HCV infection and younger age are associated with lower lipid levels among HIV-infected individuals following the initiation of ART.
We found smaller increases in lipids among patients who received tenofovir/lamivudine vs. other NRTI pairs in adjusted analyses. Prior studies on the association of NRTIs and lipids have had conflicting results. Whereas several studies have suggested there are differences associated with particular NRTIs [11,44–52], a few have not [9,28,53]. Switch studies have demonstrated decreases in lipid levels among those who changed other NRTIs to tenofovir [46–51,54,55]; however, these differences have sometimes waned over time , and did not necessarily include HDL [46,51,56,57]. In addition, switch studies are often small, and examine only one particular comparison. A meta-analysis of 48-week data from clinical trial patients found smaller increases in TC, LDL, and triglyceride levels among patients on tenofovir/emtricitabine than other NRTIs (stavudine, zidovudine, and abacavir with lamivudine); however, the other NRTIs were combined in one group and not compared separately . A large cross-sectional study suggested tenofovir was associated with lower triglyceride levels compared with those not receiving tenofovir . Our findings differed from the Swiss cohort study results that found that increasing exposure to abacavir may be associated with a decline in triglyceride levels . However, that study combined tenofovir with abacavir for analysis making interpretation of the impact of either drug difficult.
We found smaller increases in HDL levels among those who initiated tenofovir/lamivudine than those who started other NRTI pairs. This stands in contrast to a prior clinical trial that did not detect differences in HDL levels at 144 weeks among those on tenofovir/lamivudine vs. zidovudine/lamivudine . This difference in findings may be due to the small absolute difference in HDL levels. Our findings also differ from those of another RCT conducted among treatment-naive patients starting efavirenz, lamivudine, and either tenofovir or stavudine which found smaller increases in TC, LDL, and triglyceride values among patients on tenofovir, but larger increases in HDL . A prior large cross-sectional study among HIV-infected women found that use of didanosine or lamivudine was associated with higher HDL levels; however, that study was not limited to individuals on their initial ART regimen . A simplification trial of patients changed to abacavir/lamivudine vs. tenofovir/emtricabine suggested that patients who received tenofovir/emtricitabine had lower lipid levels including HDL; however, they also were more ART-experienced and slightly more likely to be receiving lipid-lowering medication thereby complicating interpretation . An RCT of patients on zidovudine or stavudine switched to abacavir or tenofovir found significantly greater decreases in mean TC, LDL, and triglycerides for patients switched to tenofovir than among those switched to abacavir, but differences in HDL levels were not significantly different . Few large longitudinal studies have evaluated differences in HDL levels associated with particular NRTIs or NRTI pairs among naive patients in routine care, which is addressed by the current study thereby providing complementary data to clinical trial results.
Didanosine/lamivudine use was associated with the greatest increase in LDL levels and didanosine/stavudine was associated with greater increases in lipid levels in sensitivity analyses that also accounted for BMI. Accounting for BMI may be particularly important in evaluating the association between lipids and NRTIs such as didanosine/stavudine, which have been shown to have a very different impact on body fat changes than other NRTIs such as abacavir/lamivudine . Whether the increased LDL associated with didanosine/lamivudine contributes to the suggested association between recent didanosine and risk of myocardial infarction  has yet to be established.
We found the greatest lipid level increases in the first 2 months after starting ART and that individual lipid levels continued to increase for different time periods. Our findings expand on prior studies that found the largest increases in lipid levels during the first 6 months of ART but did not examine the time early after ART initiation  or look beyond 12 months [30,63,64]. Our findings differs from a Ugandan study of patients on NNRTI-based regimens which found TC and HDL levels increased during the first year and then plateaued, LDL increased over 2 years, and triglyceride levels dropped and then returned to baseline at 24 months . We did not note an initial decline in triglyceride levels. These differences in triglyceride level results may be due to differences in health status among patients initiating ART in Uganda vs. the US.
Improved immune status and restoration to good health may play a role in the changes in lipid levels seen with ART [8,22]. Part of the increase in lipid levels, particularly LDL, is likely a return to prebaseline levels with ART initiation and improvement in immune status [5,22,78]. It seems unlikely, however, that this would result in a differential impact on lipid levels by antiretroviral medications. We conducted sensitivity analyses that included changes in CD4+ cell count or BMI over 6 months to see if differential improvement in health status or weight could be affecting results. Increases in CD4+ cell count were associated with small increases in TC, LDL, and non-HDL values, whereas increases in BMI were associated with large increases in TC, LDL, triglyceride, and non-HDL values. Although more limited due to smaller sample size, these sensitivity analyses demonstrated that changes in CD4+ or BMI did not explain all of the differences in the impact of individual antiretroviral medications on lipid levels.
We found that use of lipid-lowering medications increased over time, as has been seen previously . This could confound the associations between lipid levels and antiretroviral medications; however, sensitivity analyses that included adjustment for statins and other lipid-lowering medication revealed similar findings as in the main model. The overall consistency of the various analyses provides additional reassurance of the robustness of the findings.
Lipid values were measured in routine care so we could not confirm fasting status and there are different numbers of values for each lipid class. Patients were not randomized to their antiretroviral medications. As with any observational study, there may be confounding factors for which adjustment is not possible. Too few naive patients initiated ART with medications used less commonly in first regimens such as amprenavir, maraviroc, tipranavir, or darunavir to include patients on these regimens in the analyses; however, data continue to accrue. Due to small numbers, lipid-lowering medications were categorized into two classes, rather than examined individually. Finally, the study lacks information regarding genetic factors, diet, and exercise; however, we would not expect these factors to vary by particular regimen.
Strengths of this study include comprehensive clinical data and large patient numbers. Comprehensive data allowed us to censor lipid values after changes had been made to antiretroviral regimens. It has been suggested that excluding those on lipid-lowering medication would result in a biased estimate of lipid levels because these medications are most likely to be used in those with the highest serum lipid levels . However, the comprehensive data allowed us to examine the impact of lipid-lowering medications rather than simply excluding those patients. Studies have provided information on individual protease inhibitor and NNRTI agents; however, many fewer studies have examined the impact of NRTI backbones. The large sample size facilitated inclusion of over 500 women allowing us to expand on prior studies, which focused only on men [5,7,8].
Additional strengths of this study are the longitudinal study design and inclusion of only patients naive to potent ART. This is not the first study to examine the association between medications and lipid levels; however, many of the prior studies were cross-sectional in nature [31,32], and did not limit patients to their initial regimen increasing concerns about confounding in comparisons between patients by antiretroviral medications. Although inclusion of only potent ART-naive patients may limit generalizability to all HIV-infected patients, it eliminates the potential confounding due to duration or number of prior regimens . An additional strength is the inclusion of non-HDL which was not examined in many early studies and has been shown to be an important consideration in cardiovascular risk assessment, particularly in the setting of elevated triglycerides, a common problem in HIV-infected individuals.
The longitudinal study examined the association between different antiretroviral medications and lipids among a large cohort of ART-naive HIV-infected patients in routine care. Patients who initiated regimens containing tenofovir/lamivudine (or tenofovir/emtricitabine) had the smallest increases in lipid levels, including HDL. The long-term implications of these findings on cardiovascular disease risk are not yet known. Findings from this study demonstrate that comparisons of dyslipidemia and cardiovascular disease risk factors associated with antiretroviral medications should focus on individual agents rather than on class effects. This study provides additional evidence that the metabolic impact of most antiretroviral agents, particularly those used more commonly in initial regimens in the current ART era, are relatively modest.
Funding/support: This work was supported by grants from the Mentored Patient-Oriented Research Career Development Award NIAID Grant (AI-60464), the American Heart Association Grant-in-Aid Grant (09050129G), the AHRQ grant (R21HS019516), the CNICS grant (R24 AI067039), and the University of Washington Center for AIDS Research NIAID Grant (AI-27757). The funding agreements ensured the authors' independence in designing the study, interpreting the data, writing, and publishing the report.
H.M.C., M.M.K., and C.G. contributed to study design; M.M.K., M.S.S., R.M., M.M.L. contributed to data collection; H.M.C., S.V.R., B.J.F., and M.M.K. contributed to data quality and analyses; all authors contributed to manuscript development and have reviewed the manuscript.
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