{"id":5961,"date":"2009-10-05T08:12:13","date_gmt":"2009-10-05T07:12:13","guid":{"rendered":"http:\/\/moomango.co.uk\/htb\/?p=5961"},"modified":"2013-08-16T10:05:27","modified_gmt":"2013-08-16T10:05:27","slug":"lipid-and-metabolic-changes-with-arv-combinations","status":"publish","type":"post","link":"https:\/\/i-base.info\/htb\/5961","title":{"rendered":"Lipid and metabolic changes with ARV combinations"},"content":{"rendered":"

Simon Collins, HIV i-Base<\/strong><\/p>\n

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.<\/strong><\/p>\n

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.<\/p>\n

Comparative and detailed results on body composition supported DEXA\/CT scaning – probably the most important results for patient currently experiencing lipohypertrophy on existing regimens \u0096 are still scarce, even in Phase III studies for the most recently approved drugs.<\/p>\n

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). [1]<\/p>\n

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. [2]<\/p>\n

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).<\/p>\n

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). [3]<\/p>\n

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).<\/p>\n

The lipid profile of nevirapine was slightly better when compared to boosted atazanavir, in the ARTEN study, again each with FTC\/tenofovir. [4]<\/p>\n

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.<\/p>\n

The impact of the integrase inhibitor raltegravir on glycemic changes in HIV-negative volunteers, resulted in a more favourable profile compared to lopinavir\/r. [5]<\/p>\n

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.<\/p>\n

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%).<\/p>\n

Use of lipid-lowering drugs were similar (darunavir\/r: 8% [statins: 7%; fibrates 1%]; lopinavir\/r: 11% [statins: 5.5%; fibrates: 3.5%].<\/p>\n

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.<\/p>\n

References:<\/p>\n

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.<\/p>\n

    \n
  1. Heera J et al. The MERIT study of maraviroc in antiretroviral-naive patients with R5 HIV-1: 96-week results. Oral abstract TUAB103.
    \nhttp:\/\/www.ias2009.org\/pag\/Abstracts.aspx?AID=2556<\/a>
    \nSession:
    \n    http:\/\/www.ias2009.org\/pag\/PSession.aspx?s=2421 <\/a><\/li>\n
  2. 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.
    \n    http:\/\/www.ias2009.org\/pag\/Abstracts.aspx?AID=3799 <\/a><\/li>\n
  3. 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.
    \n    http:\/\/www.ias2009.org\/pag\/Abstracts.aspx?AID=3754 <\/a><\/li>\n
  4. 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.
    \nhttp:\/\/www.ias2009.org\/pag\/Abstracts.aspx?AID=3709<\/li>\n
  5. 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.
    \n    http:\/\/www.ias2009.org\/pag\/Abstracts.aspx?AID=2667 <\/a><\/li>\n
  6. 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.
    \n    http:\/\/www.ias2009.org\/pag\/Abstracts.aspx?AID=1902<\/a><\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"

    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 …<\/p>\n","protected":false},"author":4,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[4,8,27],"tags":[93],"class_list":["post-5961","post","type-post","status-publish","format-standard","hentry","category-conference-reports","category-side-effects","category-weight-diabetes-metabolic-complications","tag-ias-5th-2009"],"_links":{"self":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/5961","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/users\/4"}],"replies":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/comments?post=5961"}],"version-history":[{"count":0,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/5961\/revisions"}],"wp:attachment":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/media?parent=5961"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/categories?post=5961"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/tags?post=5961"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}