The body fat changes seen in people taking HAART do not have a single cause according to an Italian study published in the 9
Investigators suggest that factors such as sex, and treatment history could be involved in the development of fat accumulation or fat loss. The researchers, who are involved in the Italian Cohort of Antiretroviral-Naïve Patients, recruited 655 people from 34 treatment centres between September 1999 and March 2000. Study participants were followed-up every six months, with average follow-up lasting 86 weeks (range 52-107 weeks).
The study was designed to assess how often people new to anti-HIV therapy developed body shape changes, whether they developed fat loss, fat accumulation or both, and if any risk factors could be associated with these body shape changes. Fat changes were analysed by physician report.
In order to see if fat loss and fat accumulation were associated with different risk factors, and to see if different drugs carried varied risks of body shape changes, the investigators divided participants into the following categories: people with fat loss; people with fat accumulation; people with both fat loss and fat accumulation (mixed form of lipodystrophy). Treatment history divisions were as follows: people who started treatment with two NRTIs; people who subsequently added a protease inhibitor (PI) to their therapy; and, patients who did not add a PI during the entire period of follow-up.
Details of the study group’s age, sex, mode of HIV infection, hepatitis C status, and weight were also reported. In total 128 (19.6%) patients experienced some body fat changes. Abdominal fat accumulation was most frequently observed (72 people); loss of fat in the limbs (48 people) and cheeks (28) were the most commonly reported forms of lipoatrophy.
The researchers also found that HCV coinfection (present in 36% of the cohort) was a significant risk factor for development of lipoatrophy, as was older age. However, exposure to HIV by injecting drug use was associated with a lower risk of lipodystrophy, leading the authors to speculate that poorer adherence due to lower educational and income level may have affected the degree of drug exposure experienced by this group of patients. This finding tends to reinforce the view that drug-related factors play a substantial part in the development of the syndrome.
On the other hand, a gender difference not linked to treatment history also emerged. Women were significantly more likely to develop fat accumulation or a mixed syndrome of fat gain and fat loss.
When the data for HIV treatment history were analysed, investigators found that length of treatment with d4T was a significant independent risk factor for the development of lipoatrophy, but ceased to be so when other risk factors were controlled for in the analysis. An even weaker association was found with AZT use.
Adding a protease inhibitor to earlier dual NRTI therapy was found to be predictive of body shape changes, even when use of d4T, viral load and CD4 count were controlled for.
The investigators noted that abdominal fat accumulation was seen earlier in treatment, and that being overweight before starting antiretroviral therapy was a predictor of increased abdominal girth. By contrast, sunken cheeks took longer to appear and the investigators speculate “that fat loss may be a conseequence of longer exposure to A(nti) R(etroviral) T(herapy).” However, duration of exposure to protease inhibitors did not significantly increase the risk of developing lipoatrophy, suggesting a predominant role for NRTIs in the development of fat loss. Duration of exposure to indinavir was associated with development of the mixed form of lipodystrophy.
People in the study who added a protease inhibitor to a pre-existing dual NRTI combination were found to be twice as likely to develop body fat changes when compared to people who remained on dual NRTI therapy, independent of other possible risk factors such as CD4 count and switch from AZT to d4T. Once again, investigators suggest that duration of therapy may have a role, that PIs and NRTIs “cooperate in inducing” body fat changes, and that prior use of NRTIs may increase the risk of fat disturbances if a PI is added to treatment. The investigators believe that this could mean that “biological modifications induced by treatment as a whole…and not only specific drug toxicity are involved in causing adipose tissue alterations.”
Indeed, the fact that women are more likely than men to have fat gain or a combination of fat gain and loss is believed by the investigators to be evidence of the “possible existence of different pathogenic mechanisms.”
Comment
The results of this study contradict the findings of the largest randomized prospective lipodystrophy study to date, ACTG 384, which showed that the combination of d4T/ddI was associated with a significantly greater risk of lipoatrophy than AZT/3TC. However, the ACTG 384 analysis did not look at the interaction between NRTIs and PIs or NNRTIs, and has not yet subjected the data to the kind of multivariate analysis designed to tease out the effect of multiple potential influences used by the LipoICONA group.
Reference
Galli M et al Incidence of adipose tissue alterations in first-line antiretroviral therapy: the LipoICoNa study. Archives of Internal Medicine 162, 2621-2628, 2002.