Lipoatrophy improved by switching from d4T to abacavir

Graham McKerrow, HIV i-Base

Abacavir (ABC, Ziagen) represents a virologically effective replacement for d4T, PI, or NNRTI in people on successful first-line therapy, concludes a British study. The authors report that replacement of a PI or NNRTI with ABC leads to modest improvement in both cholesterol and triglycerides. Replacement of d4T with ABC leads to modest improvements in fat mass.

This was an open-label randomised study of HIV-positive individuals on a first-line therapy containing stavudine (d4T) with either a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI) and with hypercholesterolemia (defined as total cholesterol >5.2 mmol/L or >180 mg/dL) and/or lipoatrophy and with a viral load of <50 copies/mL. Patients switched d4T to abacavir (ABC) (group 1), a PI or NNRTI to ABC (group 2), or d4T and PI or NNRTI to ABC plus AZT (group 3). Patients were followed-up with fasting blood levels, dual-energy X-ray absorptiometry (DXA), and computed tomography (CT) scans for 48 weeks.

Patients were eligible for inclusion if they (1) were HIV-positive and on a first-line therapy containing d4T with either a PI or an NNRTI, (2) had hypercholesterolemia (defined as total cholesterol >5.2 mmol/L or >180 mg/dL) and/or clinical lipoatrophy, and (3) had a viral load <50 copies/mL. Lipoatrophy was assessed as described in the entry criteria for the HIV lipodystrophy case definition study, involving patient- and physician-agreed moderate or severe lipoatrophy at one or more sites.

Thirty patients were included, with 27 completing 48 weeks of therapy. One ABC hypersensitivity reaction was the only serious adverse event. All patients’ viral loads remained at <50 copies/mL. CD4 cell counts rose in groups 2 and 3 but fell modestly in group 1. Total and low-density lipoprotein cholesterol improved significantly in groups 2 and 3. Triglycerides fell significantly in group 2. In contrast, total, arm, and leg fat mass (by DXA) rose significantly in group 1 but fell modestly in groups 2 and 3. Visceral adiposity (by CT scan) was unaffected in all groups.

The study evaluated three possible approaches to manage lipid, insulin, and morphologic changes in persons on d4T plus PI-based or NNRTI-based first-line antiretroviral regimens. With all approaches, ABC maintained virologic control and significant differences in CD4 cell count were not observed. Previous studies using ABC or ABC plus AZT-based substitutions have indicated that virologic control is maintained in first-line therapy patients but less reliably in individuals with prior incomplete viral suppression of thymidine-based therapy or known archived nucleoside analogue resistance mutations. Pretreatment CD4 count and viral load do not appear to affect the efficacy of ABC-based regimens when ABC is used as a substitution agent in individuals with full viral suppression on first-line therapy.

For the management of hypercholesterolemia, total and LDL cholesterol improved significantly when the PI or NNRTI was replaced by ABC. In their Discussion, the authors write that these data are consistent with several previous reports of this substitution approach. Data from a randomised study comparing PI replacement with ABC, nevirapine, or efavirenz found declines in total cholesterol to be greatest in the group switched to ABC. These data suggest that replacement of d4T with ABC in these circumstances may lead to modest rises in total cholesterol. As with this study, a similar nonsignificant rise in total cholesterol was observed in a larger 24-week randomised study of this approach. These small rises in cholesterol and triglycerides are not of sufficient magnitude to influence cardiovascular risk meaningfully, write the authors.

None of the substitution approaches led to significant improvements in HDL cholesterol, triglycerides, insulin, or lactate over 48 weeks, although groups 2 and 3, which involved the replacement of a PI or NNRTI with ABC, indicated trends to improvement in triglycerides and insulin consistent with larger studies.

Fat mass in both arms and legs improved significantly over 48 weeks when d4T was replaced by ABC. However, this benefit was not observed when the d4T-based regimen was replaced with one containing AZT.

The authors add: “Most intriguingly, lipids and insulin levels rose in the group where fat mass recovered but fell in the populations where fat mass did not recover. This suggests that these factors are incompletely (at best) linked.”

They conclude: “In summary, replacement of d4T, PI, or NNRTI in first-line therapy patients with ABC maintains virologic control. Replacing d4T with ABC leads to improvements in limb fat mass, but these improvements are not accompanied by improvements in fasting lipids. Replacement of a PI or NNRTI with ABC is associated with improved fasting cholesterol (with trends to better triglycerides and insulin levels) but without benefits to fat mass.”

Ref: Moyle GJ, Baldwin C, Langroudi B et al. A 48-week, randomised, open-label comparison of three abacavir-based substitution approaches in the management of dyslipidemia and peripheral lipoatrophy. Journal of Acquired Immune Deficiency Syndromes May 1, 2003; 33(1):22-28.

This paper can be found at:
http://www.natap.org/2003/may/052803_4.htm