The results of this study indicate that in hyperlipidemic, virologically suppressed, immunocompetent antiretroviral-experienced patients (HIV-1 RNA <50 copies/mL, CD4+ counts >500 cells/mm3), substituting abacavir for hyperlipidemia-associated PIs in HAART regimens improves lipid profiles and maintains virologic suppression over a 28-week period. The lipid findings are consistent with those of other studies in which abacavir was substituted for PIs in HAART regimens [28–33]. However, unlike the other studies, ESS40003 evaluated a population consisting entirely of patients who were hyperlipidemic at baseline. Also, unlike two previous studies that reported lipid changes following abacavir substitution [29, 30], ESS40003 measured fasting lipids rather than lipids in a non-fasted state (which may confound results). Thus, true differences between abacavir and PI-containing regimens could be determined, and lipid criteria established by the NCEP ATP III could be applied . In addition to monitoring changes in cholesterol and triglycerides, ESS40003 measured changes in other laboratory values known to contribute to atherogenesis (apolipoproteins B and E, LDL subfractions, and indicators of changes in lipid processing [leptin and free fatty acids]) to gain a better understanding of the extent of the improvement in lipid profile following the switch to abacavir. Substitution of hyperlipidemia-associated PIs with abacavir was expected to improve lipid profiles because results of direct comparisons of abacavir/NRTI regimens with PI/NRTI regimens (same NRTIs administered) in antiretroviral-naïve patients have shown no significant effects on lipids with abacavir/NRTI-containing regimens [18–20].
Cross-trial comparisons with other abacavir-switch studies regarding lipid changes are limited by differences between studies in prevalence and severity of hyperlipidemia prior to the switch, specific PIs administered, pre-existing CAD risk factors of the particular patients enrolled, and stipulated dietary and exercise restrictions. Nevertheless, some generalizations can be made between the lipid changes noted in ESS40003 and those reported in other abacavir-switch studies [28–33]. First, as in these other studies, decreases in total cholesterol, LDL-cholesterol, and triglycerides occurred rapidly following the switch to abacavir, with statistically significant differences noted between treatment arms within 4 weeks. Second, as would be expected, the magnitude of the reduction in total- and LDL-cholesterol and triglycerides at week 28 in our study was markedly greater than that reported in studies that included normolipidemic as well as hyperlipidemic patients. Third, as in the other studies, switching from a PI to abacavir had no significant effect on HDL-cholesterol.
The small reduction in lipids observed in the PI-continuation arm may have occurred because patients were aware that their lipids were being monitored, and therefore may have exerted more self-control than usual regarding their dietary fat intake and frequency of smoking, or may have exercised more (not monitored in this study). A similar phenomenon was observed over 48 weeks in another PI-to-abacavir switch study, CNA30017 . As no change in body weight, BMI, or waist-to-hip ratio was observed in our study in either group, anthropomorphic parameters were unlikely to have accounted for the decreases in lipids observed during this study. The 28-week duration of this study may have been too short to see significant changes in BMI or waist-to-hip ratios. However, in the Swiss HIV Cohort Study, substitution of abacavir for a PI was not associated with a change in waist-to-hip ratios even after 48 weeks post-switch .
Maintenance of virologic suppression and increases in CD4+ cell count over the 24-week period following the switch to abacavir were expected in view of the lack of change in these surrogate markers previously observed in abacavir-switch studies conducted over 48 weeks to 1 year [27, 29].
The abacavir-containing regimen was generally well-tolerated, and the type and incidence of adverse events (notably fatigue and nausea) and rare occurrence of suspected abacavir-related hypersensitivity reactions were consistent with what has been reported in other clinical trials . New adverse events in the PI-continuation arm were not expected as patients had been stabilized on this treatment for >3 months. This fact may have accounted for the comparatively lower incidence of GI adverse events in the PI-continuation arm than in the abacavir-switch arm, a finding that has not been observed in direct comparisons of abacavir with PIs (indinavir or nelfinavir) administered with the same background antiretroviral drugs [18, 19, 21].
Results of the PMAQ-7 indicated significantly better Scheduling and Timing scores in the abacavir-switch arm. Significant improvement in this PMAQ-7 dimension was similarly reported at 24 weeks in the PI-to-abacavir switch study, COL30305 . Improved scores in this dimension may have been related to the simpler, twice-daily dosing of abacavir compared to the patients' previous PI-containing regimens. The proportion of patients reporting 100% adherence previously was shown to be higher at 24 weeks in one PI-to-abacavir switch study (COL30305; 92% vs 68%)  and at 48 weeks in another (CNA30017; 91% vs 76%) . In these trials, better adherence with the abacavir-containing regimen was believed to be due at least in part to the relatively lower pill count and absence of special dosing requirements incurred by abacavir-containing HAART. The absence of a significant difference in overall QOL between the abacavir-switch and PI-continuation arms was not unexpected in view of the same finding being demonstrated on the SF-36 at 24 weeks in COL30305 .
Switching to abacavir is just one of several switch strategies that have been investigated to date in an attempt to remedy hyperlipidemia in patients receiving PI-containing HAART. It is acknowledged that the ideal candidate for this switch strategy is a patient started on triple therapy, where pre-existing abacavir resistance is unlikely [30, 32]. Another switch strategy-replacement of hyperlipidemia-associated PIs with PIs that have a low likelihood of causing significant lipid elevation or adversely affecting the total cholesterol:HDL cholesterol ratio (fosamprenavir or atazanavir)-would be expected to improve lipid profiles in HIV-infected patients [6–8, 35]. Attempts to reduce lipids by switching from a hyperlipidemia-associated PI to NNRTIs have also been investigated [32, 36–43]. More favorable lipid effects appear to occur when a switch is made to nevirapine than to efavirenz [42, 43].
This study had several limitations. As patients in this study had mean CD4+ cell counts >500 cells/mm3, they were highly immunocompetent and may not be representative of typical HIV-infected patients presenting to their physician with PI-associated hyperlipidemia. The study did not evaluate the influence of NRTI background drugs on lipid changes because the patients remained on the same baseline NRTIs. This could have affected the results because stavudine is known to elevate cholesterol and triglyceride levels , whereas zidovudine and lamivudine do not. Most studies have found that switching therapy tends to be optimally effective in patients whose viral load is fully suppressed for at least 6 months rather than the 3 months in our study . This shorter pre-study time of viral suppression could have biased the virologic results against abacavir, as could allowing prior suboptimal nucleoside therapy. As we did not have information about prior NRTI combinations that many patients received pre-study, we could not assess whether these earlier NRTI combination regimens had been inadequate. Lipid data for study participants prior to their receipt of PI-containing regimens were not available to the investigators; thus, whether PIs were the cause of the patients' hyperlipidemia could not be verified. Dietary intake and physical activity assessments were not performed in this study to evaluate whether either differed between the treatment arms.
Further valuable clinical information could have been acquired from this study had switch agents in addition to abacavir been used as comparators. In the only study of this type that has been conducted to date – the Nevirapine-Efavirenz-Abacavir (NEFA) Study – a significantly lower proportion of stabilized HAART recipients (HIV-1 RNA <50 copies/mL for = 6 months) switching from a PI to abacavir developed fasting plasma triglycerides >400 mg/dL and plasma cholesterol >240 mg/dL at 12 months compared to treatment groups in which patients switched from a PI to efavirenz or nevirapine . Kaplan-Meier estimates of the likelihood of reaching the primary treatment end point (increase in HIV-1 RNA levels to ≥ 200 copies/mL, progression to AIDS, or death) in NEFA showed no significant differences between treatments. Median CD4+ cell counts increased above baseline similarly in all three treatment arms (by 39–50 cells/mm3 at 12 months). However, the abacavir-switch arm had a significantly lower incidence of adverse events than the efavirenz-switch and nevirapine-switch arms (41% vs 57% and 54%, P= 0.03), a lower incidence of neuropsychiatric adverse events than the efavirenz group (9% vs 31%; Grade 3 or 4: 0.7% vs 14%), and significantly fewer cases of discontinuation of study drug due to adverse events (6% vs 17% and 17%, P= 0.01). Overall, NEFA, like our study, indicated that abacavir was an appropriate drug to substitute for PIs in HAART regimens as long as patients were virologically suppressed pre-switch and minimally antiretroviral-experienced. Our study differed from NEFA in that all participants in ESS40003 had PI-associated hyperlipidemia at baseline (NEFA included only 7–13% with triglycerides >400 mg/dL and 21–25% with total cholesterol >240 mg/dL) and because our study used a less stringent definition of virologic failure (HIV-1 RNA >1000 copies/mL on two occasions at least 1 week apart vs. HIV-1 RNA ≥ 200 copies/mL at ≥ 16 weeks, with subsequent confirmation [NEFA]).