Replacement of protease inhibitor results in improved blood fat levels, but doesn't stop fat loss

Patients on a stable anti-HIV drug regimen containing a protease inhibitor (PI) may experience improvements in blood fat levels after replacing the PI with abacavir (Ziagen), efavirenz (Sustiva) or nevirapine (Viramune), according to a subanalysis of a Spanish clinical trial. However, the study, published in the 10^th June edition of AIDS, also showed that switching to a PI-sparing combination did not improve blood sugar levels or body fat distribution.

Metabolic changes, such as elevations in blood fat (lipid) and sugar levels, are common side-effects of antiretroviral therapy, as are changes in the distribution of body fat (lipodystrophy). Since previous studies have linked PI-based therapy to these effects, investigators from Spain carried out a subanalysis of the NEFA trial to examine the effects of replacement of PIs with other drugs on these side-effects.

The NEFA trial is a randomised study designed to compare the effects of substitution of PIs by abacavir, efavirenz or nevirapine. For this substudy, levels of two different types of fat, cholesterol and triglycerides, were measured every three months in 90 patients. The investigators also measured blood glucose levels and the degree of fat redistribution by physical examination.

“Our analysis suggests that replacing a PI with nevirapine, efavirenz or abacavir results in an improved metabolic profile, especially in non-lipodystrophic patients,” conclude the study’s authors. “In contrast, PI replacement did not prove to be a good strategy for stopping the peripheral fat atrophy process.”

Overall, replacement of a PI led to improvements in blood fat levels at 24 months. The 32 patients replacing a PI with efavirenz showed a median increase of 15% in the concentration of high-density lipoprotein (HDL or ‘good’) cholesterol (p = 0.001). Similarly, the 29 replacing the PI with nevirapine showed an increase of 21% (p

The investigators also saw a decrease in the ratio of total to HDL cholesterol, which is linked to the risk of cardiovascular disease. Patients switching from a PI to efavirenz showed a decrease of 14% (p

“Several observational studies have concluded that this is the best single variable of the traditional lipid profile for predicting cardiovascular events,” the authors explain. “On this basis, we believe that the lipid changes observed in our two NNRTI-containing groups might be somewhat more cardioprotective than those seen in the abacavir-containing combination.”

The investigators estimated the levels of low density lipoprotein (LDL or ‘bad’) cholesterol by subtracting the HDL value from the total cholesterol level. The amount of non-HDL cholesterol decreased in both the efavirenz (11%; p

Overall, these results suggest that switching to a PI-sparing regimen leads to improved cholesterol levels. “Abacavir seemed to exert a stronger lowering power on the total and non-HDL cholesterol fraction, especially when compared to nevirapine,” conclude the researchers. “On the other hand, both efavirenz and nevirapine showed an evident beneficial effect on HDL cholesterol levels and the total cholesterol / HDL cholesterol ratio at the end of the study, which was not seen in those allocated to abacavir.”

In contrast to the effects on cholesterol, the investigators noted that improvements in triglyceride levels were transient. While levels decreased in all three groups after twelve months (p

The investigators also noted that the patients with moderate or severe lipodystrophy at the start of the study showed less impressive changes in lipid levels. In addition, there were no significant improvements in lipodystrophy across all the patients following replacement of the PI, since the proportions of patients with lipodystrophy did not change over time.

Twenty-four of the patients also underwent dual energy X-ray absorptiometry (DEXA) scans at baseline and at 12 months. This confirmed the results from physical examination, showing a loss of fat in the limbs.

“Altogether, the analysis of body habitus changes by objective measurements indicated that there was either no recovery of lipodystrophy or a worsening of peripheral lipoatrophy during the study period,” write the investigators.

The investigators postulate that the failure of switching to a PI-sparing regimen to reverse body fat changes may be due to the inclusion of the nucleoside reverse transcriptase inhibitor d4T (stavudine, Zerit) in most (84%) of drug regimens taken by patients with lipodystrophy. d4T is known to cause the loss of peripheral fat. It is possible that the widespread use of the drug in this study continued to cause loss of fat from the limbs after the PI was stopped.

Despite robust changes in measures of lipid abnormalities, the study did not reveal similar effects on blood sugar levels. Although measurements of glucose levels showed small increases in the efavirenz group (7%; p

In addition, although levels of resistance to the hormone insulin showed a trend towards improvement, the changes did not reach statistical significance. Insulin resistance is a common feature of the development of diabetes, which can also develop as a side-effect of antiretroviral therapy.

This study is limited by the lack of a comparison group who did not switch to a PI-sparing regimen. In addition, the investigators acknowledge that “the statistical power to detect changes over time … proved to be limited. Hence, we cannot rule out the possibility of true changes in these variables not detected by our analyses.”