Lipid and metabolic changes with ARV combinations
Simon Collins, HIV i-Base
Lipid results can be complicated to interpret, especially between studies, given the lack of consistency in the method of reporting. Changes in lipid parameters, both from baseline and between-arm comparisons can often be statistically significant, for differences that are modest in absolute (and therefore clinical) terms.
While total cholesterol:HDL ratio is most useful in terms of having an impact on Framingham-based calculation of cardiovascular risk, other studies report results by the percentage of patients reaching guideline target for starting lipid-lowering drugs (LLDs). This is further complicated, particularly in treatment-naive studies by a return-to-health effect that reverses earlier HIV-related metabolic changes.
Comparative and detailed results on body composition supported DEXA/CT scaning – probably the most important results for patient currently experiencing lipohypertrophy on existing regimens are still scarce, even in Phase III studies for the most recently approved drugs.
The MERIT study reported more favourable lipid parameters in patients using maraviroc compared to efavirenz (each with FTC/TDF) evaluated by the percentage of each group that exceeded NCEP guidelines for lipid lowering therapy. At week 96, in the maraviroc vs efavirenz groups respectively, approximately 11% vs 39% for total cholesterol; 6% vs 27% for LDL-cholesterol (>3.4mmol/L), both p<0.0001; and 16% vs 19% triglycerides (NS). 
Although the main finding of the ALTAIR study was the under-performance of a 4-nuke arm, the lipid profile of efavirenz produced greater increases in HDL-cholesterol (but also conversely glucose) compared to atazanavir/r. 
Metabolic changes were measured by DEXA and CT imaging. This was a three-arm open-label study that compared atazanavir/r to efavirenz and to AZT/abacavir all using FTC/tenofovir, in just over 300 treatment-naive patients. The four-nuke combination was significantly less effective virologically, but also (compared to atazanavir/r) for HDL-cholesterol, LDL-cholesterol, total cholesterol and glucose changes. The inclusion of AZT resulted in significant peripheral fat loss in arm, leg and total body fat and a reduction in the VAT:SAT ratio. Broadly similar responses were seen in the efavirenz and atazanavir/r groups (+0.6% and +1.7%) in limb and total body fat, though efavirenz produced a significantly greater increase in HDL (+0.18 vs +0.09, p = 0.006) and glucose (+0.34 vs -0.03, p<0.001).
The impact of 100mg ritonavir on lipid levels when boosting atazanavir (with background 3TC/abacavir) was shown in the ARIES study. This study randomised 419 patients, who were initially suppressed for 36 weeks on atazanavir/r (300/100mg daily), to either continue on the boosted regimen or switch to unboosted atazanavir (400mg daily). 
At 48 weeks after the switch, median total cholesterol, LDL-cholesterol and triglycerides declined in the unboosted group while continuing to increase (slightly) in the boosted arm. HDL-cholesterol remained unchanged in each arm (both slightly higher compared to study baseline: median +10mg/dL). Use of lipid-lowering drugs was similar (16% vs 13% in the boosted vs unboosted groups).
The lipid profile of nevirapine was slightly better when compared to boosted atazanavir, in the ARTEN study, again each with FTC/tenofovir. 
Lipid changes at week 48 showed a -0.24% reduction in the TC:HDL ratio in the nevirapine group compared to an increase of +13% in the atazanavir/r group. This was driven by proportionally greater increases in HDL-cholesterol, as total cholesterol, LDL-cholesterol, HDL-cholesterol all increased in both groups. Although statistically significant (p<0.0001) both changes were modest terms in absolute terms. Triglycerides increased by 28mg/dL in the atazanavir/r group but remained similar to baseline levels in the nevirapine group. Previously, in the CASTLE study, ritonavir-boosted atazanavir showed a small improvement in TC:HDL ratio.
The impact of the integrase inhibitor raltegravir on glycemic changes in HIV-negative volunteers, resulted in a more favourable profile compared to lopinavir/r. 
Changes in insulin sensitivity and glucose disposal, measured by euglycemic clamps, were recorded in in a 2-phase cross-over study, separated by a 2-week wash-out period, in HIV-negative individuals exposed to either lopinavir/r or raltegravir (each for two weeks). Supporting results from earlier studies, the lopinavir/r group experienced a mean reduction of insulin sensitivity of -16% compared to no changes seen during raltegravir exposure (p=0.018). Total cholesterol, LDL-cholesterol and triglycerides all increased significant during lopinavir/r exposure (by about 14%, 15% and 37%, respectively) compared to during raltegravir exposure, when no significant changes were seen. Mean levels of adiponectin, an insulin-sensitising adipokine, also increased in the lopinavir/r groups (by 15%, p=0.03 compared to raltegravir) indicating that peripheral fat cells were working harder to become insulin sensitive during lopinavir/r exposure.
Finally, lipid changes for darunavir/r (800mg/100mg once-daily) in the ARTEMIS study were compared to lopinavir/r (in both once- and twice-daily regimens). At 96 weeks, total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides all increased from baseline in both arms, although the increases in both total cholesterol and triglycerides were significantly greater for lopinavir/r (TC: +28 vs +35; TG +18 vs 65 mg/dL), with all grade 2-4 lipid changes higher in the lopinavir/r vs darunavir/r groups (~15% vs 8%).
Use of lipid-lowering drugs were similar (darunavir/r: 8% [statins: 7%; fibrates 1%]; lopinavir/r: 11% [statins: 5.5%; fibrates: 3.5%].
Although patients in the darunavir/r arm had greater increases in weight (+2.5kg [IQR -0.2, +6.1kg] versus 1.3kg [-1.0, +5.0kg]; p=0.006) and in median BMI (0.9kg/m2 vs 0.4kg/m2; p< 0.006) these differences not considered clinically relevant. Symptomatic lipodystrophy changes (fat loss or gain, investigator judged) were reported in <1% of patients in each group.
Unless stated otherwise, all references are to the Programme and Abstracts of the 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. 19-23 July 2009, Cape Town.
- Heera J et al. The MERIT study of maraviroc in antiretroviral-naive patients with R5 HIV-1: 96-week results. Oral abstract TUAB103.
- Cooper D et al. Safety and efficacy of three different combination antiretroviral regimens as initial therapy for HIV infection: week 48 data from a randomised, open-label study. Late-breaker poster abstract LBPEB09.
- Squires K et al. Similar efficacy and tolerability of atazanavir (ATV) compared to ATV/ritonavir (RTV, r), each in combination with abacavir/lamivudine (ABC/3TC), after initial supression with ABC/3TC + ATV/r in HIV-1 infected patients: 84 week results of the ARIES trial. Late breaker abstract WELBB103.
- Soriano V et al. Prospective comparison of nevirapine and atazanavir/ritonavir both combined with tenofovir DF/emtricitabine in treatment-naive HIV-1 infected patients: ARTEN study week 48 results Late breaker poster abstract LBPEB.
- Randell P et al. The impact of raltegravir and lopinavir/ritonavir on lipids, adiponectin and peripheral glucose disposal in HIV negative subjects. Poster abstract TUPEB171.
- Baradli E et al. Effects of once-daily darunavir/ritonavir versus lopinavir/ritonavir on lipid parameters and anthropometrics in treatment-naive HIV-1-infected ARTEMIS patients at week 96. Poster abstract MOPEB034.