A prospective, 96‐week study of the impact of Trizivir^®, Combivir^®/nelfinavir, and lamivudine/stavudine/nelfinavir on lipids, metabolic parameters and efficacy in antiretroviral‐naive patients: effect of sex and ethnicity

Abstract

To compare the lipid and metabolic effects, efficacy, and safety of twice-daily regimens of Trizivir s (abacavir 300 mg/lamivudine 150 mg/zidovudine 300 mg triple nucleoside tablet; TZV), Combivir s (lamivudine 150 mg/zidovudine 300 mg combination tablet; COM) 1 nelfinavir (NFV), and stavudine (d4 T) 1 lamivudine (3TC) 1 NFV. Study designAn international, phase 4, open-label, parallel-group, 34-centre study was conducted in 254 nondiabetic, antiretroviral-naive, HIV-infected out-patients with an HIV-1 RNA level of 41000 HIV-1 RNA copies/mL and 200 000 copies/mL and a CD4 cell count of 450 cells/mL. MethodsPatients were randomized 1 : 1 : 1 to TZV twice daily (n 5 85), COM/NFV 1250 mg twice daily (n 5 88), or d4T 40 mg 1 3TC 150 mg 1 NFV 1250 mg twice daily (n 5 81) for 96 weeks. Treatments were compared using analysis of covariance (ANCOVA) with regard to changes from baseline in fasting lipids in the total population and in sex and ethnic subgroups. The proportions of patients achieving HIV-1 RNA o50 and o400 copies/mL were compared using a 95% confidence interval (CI) on the difference between proportions. ResultsThe study population was diverse (50% female, 40% black and 37% Hispanic). Mean baseline lowdensity lipoprotein (LDL) cholesterol was 99 mg/dL, HIV-1 RNA was 4.43 log 10 copies/mL and CD4 cell count was 355 cells/mL. At week 96, fasting LDL cholesterol changed minimally in the TZV group [least square mean (LSM) change from baseline, À 8 mg/dL], but increased with d4T/3TC/NFV and COM/NFV ( 1 29 and 1 19 mg/dL, respectively; Po0.001 versus TZV). Week 96 LDL-cholesterol levels were significantly lower in the TZV group than in the other two treatment groups in women and men and lower than in the d4T/3TC/NFV group in Hispanic and black patients. In black patients, the week-96 LSM change from baseline in LDL cholesterol was significantly less with TZV than with d4T/3TC/NFV ( 1 1 vs 1 39 mg/dL; P 5 0.003). Total cholesterol4200 mg/dL occurred in a smaller proportion of patients receiving TZV (30%) compared with COM/NFV (50%) or d4T/3TC/NFV (60%; P 5 0.005 vs TZV). High-density lipoprotein (HDL) cholesterol did not change markedly with any treatment. Although triglycerides increased, they changed least in women and Hispanic patients receiving TZV. Virological and CD4 responses to the treatments were similar in the total population and in the subgroups. Diarrhoea was reported more often in the NFV arms and nausea in the ZDV arms. 85 ConclusionsOver 96 weeks, TZV twice daily has significantly less effect on LDL cholesterol than COM/NFV or d4T/3TC/NFV twice daily, especially in women and black patients, and is associated with similar virological and CD4 responses.

HAART-Associated Dyslipidemia Varies by Biogeographical Ancestry in the Multicenter AIDS Cohort Study

“…The extent to which these metabolic side effects, like dyslipidemia, vary in different ethnic or ancestral populations has been demonstrated by a number of studies, but the racial effects seen are not necessarily consistent across studies. [25][26][27] In general, these studies found that whites had more atherogenic lipid profiles in response to HAART than blacks or hispanics. Overall our results agree with these findings, but the HAART-associated change in specific lipid phenotypes does vary from previous reports.…”

“…[16][17][18][19][20][21][22][23][24] Previous studies associating dyslipidemia with specific drug combinations used in HAART have also shown that the extent of dyslipidemia tends to vary between self-reported racial populations. [25][26][27][28] Serum lipid levels, atherosclerosis, and CVD risk are all known to vary by race in the general population and polymorphisms in genes involved in cholesterol transport and metabolism may play a role in this variation. [29][30][31][32][33][34][35][36] Investigating lipid patterns by self-reported race may be complicated by the heterogeneous genetic profiles of individuals in those self-classified populations.…”

Recruitment and Retention of Diverse Populations in Antiretroviral Clinical Trials: Practical Applications from the Gender, Race And Clinical Experience Study

“…The Context Study, which assessed treatment-experienced patients, reported a discontinuation rate of 47% in women compared with 22% in men; however, women comprised only 15% of the 315 patients enrolled, limiting the interpretation of these data. 9 Additionally, in a study that enrolled 254 patients, including a high proportion of women (50%), black (40%), and Hispanic (37%) treatment-naïve patients, Kumar et al 18 reported an overall discontinuation rate of 49%; specific differences by sex were not reported. The Women First Study was specifically designed to assess the efficacy and safety of combination ARV therapy in protease inhibitor-naïve women and also to evaluate treatment compliance and continued study participation.…”

Effects of Darunavir/Ritonavir-Based Therapy on Metabolic and Anthropometric Parameters in Women and Men Over 48 Weeks

“…Fasting triglyceride elevations were more common in men than women, as has been observed in other ARV trials that enrolled either treatment-naïve or treatment-experienced patients. [4][5][6][7] The incidence of LDL elevations was numerically higher in women than men; this is supported by the cross-sectional FRAM (Fat Redistribution And Metabolic change) study, which recently demonstrated that HIV-infected women had higher LDL levels compared to uninfected women. In contrast, HIV-infected men had lower LDL levels than uninfected men, 13,14 suggesting the LDL elevations may be more prevalent in HIV-infected women than men.…”

“…[4][5][6][7] For instance, men receiving ARV therapy are more commonly reported to develop hypertriglyceridemia compared to women. [5][6][7] Few of these trials, however, have enrolled a population of women large enough to draw definitive genderbased conclusions regarding metabolic effects of individual ARV agents.…”