dolutegravir and lipids

Several of the HIV drugs are associated with adverse lipid effects, as well as metabolic (eg, insulin resistance/diabetes) and cardiovascular complications. A recent study looked at the effects of dolutegravir (an integrase strand transfer inhibitor, INSTI) on cholesterol ( see hiv dolutegravir lipids clin drug invest 2015 in dropbox, or Clin Drug Investig (2015) 35:211–219). In this analysis they looked at 4 clinical trials of Rx-naive patients put on dolutegravir (DTG) and compared the lipid outcomes after 48 weeks to: efavirenz (EFV), raltegravir (RAL), or darunavir/ritonavir (DRV/r). In all of these studies dolutegravir was at least non-inferior clinically to these other agents. all of these meds were in combo with either tenofovir/FTC (TDF/FTC) or abacavir/3TC (ABC/3TC) as backbone therapy. details:

--1118 patients: median age 37, 85% male, 75% white,  and randomized to dolutegravir 50mg qd in the 4 studies. approx 33% were on backbone therapy of abacavir/3TC.

--for dolutegravir, the mean LDL increased from 94.1 mg/dl by 4.8 mg/dl; HDL increased from 43.9 mg/dl by 3.6 mg/dl; triglycerides increased from 114.7 mg/dl by 8.7 mg/dl, but the total cholesterol/HDL ratio (a better epidemiologic predictor of future cardiac events) improved from 3.9 by decreasing 0.1.

--for raltegravir, the data were pretty much the same

--for efavirenz, the mean LDL increased from 92.7 mg/dl by 13.1 mg/dl; HDL increased from 43.6 mg/dl by 8.0 mg/dl; triglycerides increased from 111.2 mg/dl by 18.68 mg/dl​, but the total cholesterol/HDL ratio improved from 3.9 by decreasing 0.1.

--for darunavir/ritonavir, the mean LDL increased from 91.1 mg/dl by 3.1 mg/dl; HDL increased from 43.5 mg/dl by 2.2 mg/dl; triglycerides increased from 117.9 mg/dl by 33.1 mg/dl​, but the total cholesterol/HDL ratio worsened from 4.1 by increasing 0.4.

--the smaller effect of dolutegravir and raltegravir on lipids was independent of which backbone therapy was used.

prior studies have found that raltegravir has fewer effects on lipids than either atazanavir/ritonavir (ATV/r) or darunavir/ritonavir, all in combination with TDF/FTC  (eg, see http://dx.doi.org/10.1093/cid/civ193​ ). so, the above study gives even further impetus to using dolutegravir (which, as opposed to raltegravir, is once-a-day and less likely to develop resistance, and has the same lipid effects). the issue of lipid effects becomes even more important potentially as people are living longer with HIV and will be more susceptible to other, non-HIV chronic diseases. A recent analysis of the ACTG A5257 study with 1797 patients lent further support, finding that the clinical response of patients randomized to RAL, ATV/r, or DRV/r were similar but that the RAL group had less change in lipids than the other regimens. To my calculations, the cholesterol/HDL ratios were decreased from 4.04 by 0.23 with ATV/r, decreased from 3.87 by 0.09 by DRV/r and decreased from 4.01 by 0.41 !! with RAL, also suggesting that RAL was the best in terms of lipids. (see hiv lipid metab effects ACTG A5257 clin inf dis 2015 in dropbox, or doi.org/10.1093/cid/civ193 )

so, the big question is whether these changes in lipids matter. the above studies have actually found that with efavirenz the cholesterol/HDL ratio improved, and I had always been under the impression that EFV is especially bad for lipids. a recent review of the effects of EFV on lipids also has pretty consistently found dramatic increases in LDL but even more so of HDL, and improved  cholesterol/HDL ratios (see hiv med lipid effects j antivir 2012 in dropbox, or doi.org/10.4172/jaa.1000052​ ). A related concern is voiced in my recent blogs about some HDL being pro-atherosclerotic, and we do not know if the HDL increases above were in fact protective. so, the picture is still pretty muddy (as it often is with surrogate markers). and the ACTG A5257 study above did not find any difference in the incidence of metabolic syndrome, a more proximate marker of clinical disease, with baseline of 21% and all groups increasing 22% at 96 weeks.. the data on clinical cardiovascular disease is mixed. most studies have shown an increase incidence just by having HIV, by about 50%, especially MI. there are still outstanding questions about the role of antiretroviral agents. the data is probably strongest that ABC is associated with cardiovascular events, but not all studies show that, and there may well be selection bias as to which patients were on which agent.  in terms of protease inhibitors, there are clinical outcome data that ATZ/r and DRV/r are associated with fewer cardiac events. no clinical outcome data that i have seen regarding EFV.

so, bottom line: it is pretty clear that the INSTIs are taking over. 4 of the 5 first-line treatments in the recent guidelines (see http://gmodestmedblogs.blogspot.com/2015/04/updated-hiv-guidelines-2015.html  ) involve INSTIs (2 of them specifically use dolutegravir). Dolutegravir is a great drug, at least as effective as any other single agent we have, is pretty unlikely to developing HIV resistance, is really well tolerated, and is a single pill once a day (to be added to TDF/FTC or ABC/3TC). this study shows that it is lipid neutral, which is likely a good thing. i have appended a blog from last year of one of the dolutegravir studies of its clinical efficacy.

one issue that i would add as a tangent (but may be very important clinically) came out in the CROI meeting of 2015: the finding of significant renal toxicity in the D:A:D trial (a large trial assessing adverse events of HIV drugs), where 23560 patients were followed 6.3 years, finding that there was persistent increase in chronic kidney disease in those on tenofivir (97%), atazanavir/ritonavir (320%!!!), and lopinavir/ritonavir (140%). for abstract, see http://www.croiconference.org/sessions/exposure-antiretrovirals-arvs-and-development-chronic-kidney-disease-ckd . this further degrades atazanavir/ritonavir as my go-to protease inhibitor (especially with the above probable inferiority to dolutegravir for lipids), and raises even more concerns about combinations of atazanavir with tenofivir.

see the dolutegravir Flamingo study: http://gmodestmedblogs.blogspot.com/2014/04/dolutegravir-for-hiv-flamingo-study.html