d4T fat wasting risk rises with baseline triglycerides

The risk of developing lipoatrophy (fat wasting) during treatment with d4T (stavudine, Zerit) appears to be highest in individuals with high baseline triglyceride levels, in persons aged 40 or over, and in individuals who receive the Zerit immediate release formulation of the drug, according to an analysis of two studies which compared Zerit immediate and prolonged release formulations.

d4T has been associated with lipoatrophy (fat loss) for more than five years, and last year British HIV Association guidelines recommended avoiding its use in initial therapy due to concerns over this stigmatising side-effect.

However, d4T is a potent nucleoside analogue that is well tolerated in most other respects. Defining a group of individuals at lower risk of developing lipoatrophy when treated with the drug might allow d4T to be used with more confidence by clinicians and people with HIV.

A poster presentation at the recent Eleventh Conference on Retroviruses and Opportunistic Infections in San Francisco from Bristol-Myers Squib (BMS), which manufactures Zerit, sought to address this question using data from studies comparing the current formulation of Zerit, stavudine immediate release (IR), with stavudine prolonged release capsule (PRC) - as it is marketed in Europe - or stavudine XR, as it is marketed in the US. Despite this once-daily formulation having been approved in both Europe and the US late in 2002, the drug has yet to become readily available. According to BMS, this is due to its complex manufacturing process.

This poster took data from two randomised, double-blind, placebo-controlled studies (096 and 099, which each lasted 48 weeks) that compared safety and efficacy of Zerit IR to the PRC formulation - in combination with lamivudine (3TC, Epivir) and efavirenz (Sustiva) - in antiretroviral-naïve patients, and attempted to identify factors that predicted fat loss. Dosing for each arm was: stavudine PRC 100 mg once daily or stavudine IR 40 mg twice daily with 3TC 150 mg twice daily and efavirenz 600 mg once daily.

At baseline, participants in all studies had similar characteristics: about one-third were women, just under half were white, median viral load was 4.76-4.79 log₁₀ copies/ml and median CD4 count was 320-323 cells/mm³. Only those with available fasting baseline triglyceride levels were included in the analysis. Lipoatrophy was investigator-defined and included facial or limb subcutaneous fat loss or wasting.

After looking at the following variables - baseline triglycerides, baseline glucose, age, body mass index, treatment with Zerit IR, sex, race, baseline viral load, baseline CD4 count, and baseline waist circumference, the researchers found that only three factors were significantly associated with lipoatrophy. These were: use of Zerit IR (p=0.003); age over 40 (p=0.002) and baseline triglycerides above 200mg/dL (2.25mmol/L) (p=0.029).

One third of those with all three risk factors developed lipoatrophy, and one in five with two out of three risk factors developed lipoatrophy, suggesting that multiple host factors predispose to the development of lipoatrophy during d4T treatment. By contrast, in the Zerit PRC arms, one in eight of those with all three risks factors for lipoatrophy suffered fat loss (7.1% incidence of lipoatrophy), and 4.4% of those aged below 40 with triglycerides above 200mg/dL developed lipoatrophy after exposure to Zerit PRC, compared to 21.9% of those exposed to Zerit IR. However, the degree of reduction in incidence of lipoatrophy was not consistent: whereas 10.2% of those without other risk factors exposed to Zerit IR developed lipoatrophy, 7.1% of those without other risk factors exposed to Zerit PRC developed lipoatrophy.

Although not all previous studies have confirmed a particular role for stavudine in fat wasting, those that have found a role concluded that length of time on stavudine was often the most significant factor. These data are not included in the BMS poster - for instance, no differentiation is made between those exposed only in the 48-week studies and those in the rollover study - and it is possible that their conclusions do not take this into account.

The authors highlight a number of limitations to these data. Since this is a post-hoc analysis, any treatment with lipid-lowering or insulin-sensitising agents at baseline cannot be taken into account. Additionally, since lipoatrophy was defined only by the study doctors, and not independently through DEXA or other body imaging scans, it is possible that the incidence of lipoatrophy is not accurately defined, and may be underreported.

Further information on this website

d4T dose reduction improves lipoatrophy in Thai patients - news story

Fat wasting faster and greater with d4T - news story

Study finds d4T use, but not total exposure to NRTIs, associated with lipodystrophy - news story

d4T - overview

Body fat changes on HAART (lipodystrophy) - treatments