By: Dr. Geoffrey Modest<\/b><\/p>\n
Several\u00a0of the HIV drugs are associated with adverse lipid effects, as well as metabolic (eg, insulin resistance\/diabetes)\u00a0and cardiovascular complications.\u00a0A recent study\u00a0looked at the effects of dolutegravir (an integrase strand transfer inhibitor, INSTI)\u00a0on cholesterol ( see\u00a0Clin Drug Investig (2015) 35:211\u2013219<\/strong>). In this analysis\u00a0they looked at 4 clinical trials of Rx-naive patients put\u00a0on dolutegravir (DTG)\u00a0and compared the lipid outcomes after 48 weeks to: efavirenz (EFV), raltegravir (RAL), or darunavir\/ritonavir (DRV\/r). In all of these studies dolutegravir was\u00a0at least non-inferior clinically\u00a0to these other agents. all of these\u00a0meds were in combo with either tenofovir\/FTC (TDF\/FTC)\u00a0or abacavir\/3TC (ABC\/3TC)\u00a0as backbone therapy. Details:<\/p>\n –1118 patients:\u00a0median age 37, 85% male, 75% white, \u00a0and\u00a0randomized to dolutegravir 50mg qd in the 4 studies. Approx 33% were\u00a0on backbone therapy\u00a0of abacavir\/3TC.<\/p>\n –for dolutegravir, the mean LDL increased from 94.1 mg\/dl by 4.8 mg\/dl; HDL increased from 43.9\u00a0mg\/dl by 3.6\u00a0mg\/dl;\u00a0triglycerides increased from 114.7\u00a0mg\/dl by 8.7 mg\/dl, but the total cholesterol\/HDL ratio (a better\u00a0epidemiologic predictor of future cardiac events) improved from 3.9 by decreasing 0.1.<\/p>\n –for raltegravir, the data were pretty much the same<\/p>\n –for efavirenz,\u00a0the mean LDL increased from 92.7 mg\/dl by 13.1\u00a0mg\/dl; HDL increased from 43.6\u00a0mg\/dl\u00a0by 8.0\u00a0mg\/dl;\u00a0triglycerides increased from 111.2\u00a0mg\/dl\u00a0by 18.68\u00a0mg\/dl\u200b, but the total cholesterol\/HDL ratio improved\u00a0from\u00a03.9 by decreasing 0.1.<\/p>\n –for darunavir\/ritonavir,\u00a0the mean LDL increased from 91.1 mg\/dl by 3.1\u00a0mg\/dl; HDL increased from 43.5\u00a0mg\/dl\u00a0by 2.2\u00a0mg\/dl;\u00a0triglycerides increased from 117.9\u00a0mg\/dl\u00a0by 33.1\u00a0mg\/dl\u200b, but the total cholesterol\/HDL ratio worsened\u00a0from 4.1 by increasing 0.4.<\/p>\n –the smaller\u00a0effect of dolutegravir and raltegravir on lipids\u00a0was independent of which\u00a0backbone therapy was used.<\/p>\n Prior studies have found that raltegravir has fewer effects on lipids\u00a0than either atazanavir\/ritonavir (ATV\/r)\u00a0or darunavir\/ritonavir, all in\u00a0combination\u00a0with TDF\/FTC\u00a0\u00a0(eg, see\u00a0here\u200b<\/a>). 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).\u00a0the issue of lipid effects becomes even more important potentially\u00a0as people are living longer with HIV and will be more susceptible to other, non-HIV chronic diseases.\u00a0A recent analysis of the ACTG A5257 study with 1797 patients lent\u00a0further support, finding\u00a0that the clinical response of patients randomized to RAL, ATV\/r, or DRV\/r\u00a0were 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\u00a0doi.org\/10.1093\/cid\/civ193<\/a>)<\/p>\n The big question\u00a0is whether these changes in lipids matter. The above studies have actually found that with\u00a0efavirenz the cholesterol\/HDL ratio improved, and I had always been under the impression that EFV is especially bad for lipids.\u00a0A recent\u00a0review of the effects of EFV on\u00a0lipids also has pretty consistently found dramatic increases in LDL but\u00a0even more so of HDL, and improved\u00a0 cholesterol\/HDL ratios (see\u00a0doi.org\/10.4172\/jaa.1000052\u200b ). A related concern is voiced in my recent blogs about some HDL being pro-atherosclerotic,\u00a0and 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\u00a0did not find any difference in the incidence of metabolic syndrome, a more proximate marker of clinical disease,\u00a0with\u00a0baseline of 21% and all groups increasing 22%<\/strong> at 96 weeks. The data on clinical cardiovascular disease is mixed. Most studies have shown an increase incidence just by having\u00a0HIV, by about 50%, especially MI. There are still outstanding questions about the role of antiretroviral agents. The\u00a0data are\u00a0probably 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. \u00a0In terms of protease inhibitors, there are clinical outcome data that ATZ\/r and DRV\/r are associated with fewer cardiac events. No clinical outcome\u00a0data that I have seen regarding EFV.<\/p>\n 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\u00a0here<\/a>) involve INSTIs (2 of them specifically use dolutegravir).\u00a0Dolutegravir is a great drug, at least as effective as any other single agent we have, is pretty unlikely to developing HIV resistance,\u00a0is 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. See\u00a0a blog post<\/a> from last year of one of the dolutegravir studies of its clinical efficacy.<\/p>\n One issue that I would add as a tangent (but may be very\u00a0important clinically)\u00a0came out in the CROI meeting of 2015:\u00a0the 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\u00a0(97%), atazanavir\/ritonavir (320%!!!), and lopinavir\/ritonavir (140%). For abstract, see\u00a0here<\/a>. This further degrades atazanavir\/ritonavir as my go-to protease inhibitor (especially with the above probable\u00a0inferiority to dolutegravir for lipids), and raises even more concerns about combinations of atazanavir with tenofivir.<\/p>\n","protected":false},"excerpt":{"rendered":" By: Dr. Geoffrey Modest Several\u00a0of the HIV drugs are associated with adverse lipid effects, as well as metabolic (eg, insulin resistance\/diabetes)\u00a0and cardiovascular complications.\u00a0A recent study\u00a0looked at the effects of dolutegravir (an integrase strand transfer inhibitor, INSTI)\u00a0on cholesterol ( see\u00a0Clin Drug Investig (2015) 35:211\u2013219). In this analysis\u00a0they looked at 4 clinical trials of Rx-naive patients put\u00a0on […]<\/p>\n