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Lipoatrophy Didn't Improve: switch to PI-Sparing
Reported by Jules Levin
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Before discussing this PI switch study, I just finished up from a 4pm interactive oral program where I was honored to sit on a panel with several other doctors, researchers, and community. We discussed in separate discussions when to begin HIV therapy, HCV/HIV coinfection and salvage HIV therapy. Of course, I was on the panel discussing HCV/HIV coinfection, where we discussed a case of a woman with coinfection who was an IVDU. Numerous community and doctors from France, the US, and Italy all came to the microphone & up to me to talk. Clearly, the issue of coinfection is very large, much larger than many realize. The Italian doctor presenting the case said 70% of Itlaians with HIV also have HCV and 96% getting HOV by IVDU also have HCV!!! I'm off to a dinner now but would like to briefly comment on important new information reported at this afternoon's 2pm oral session on lipodystrophy. G Barbaro, an Itlaian reseacrher, reported on a large study of HIV-infected patients (87% were cigarette smokers) who received either a PI or a NNRTI regimen. Patients receiving the PI regimen were at statistically significant greater risk for heart disease. The risk started to set in by 18-20 months on therapy. There appears to be a lag time but 20 months is pretty quick. There were 23 cases of coronary heart disease in the PI group vs I think 2 in the NNRTI group by the end of followup which I think was 42 months. The patients getting heart disease were young. David Wohl, MD, UNC, is covering lipodystrophy and metabolics here for NATAP and he will file a report for you soon. HCF Cote, a researcher from Vancouver, Canada reported on an assay she uses to detect reduced mitochondria DNA (mtDNA). She reported finding that d4T and ddI reduce mtDNA. Question that have not been clearly answered is how much mtDNA reduction leads to symptoms and is there a connection with lipodystrophy.
In an important study presented this morning at the 10:30 oral session the Spanish research group (Gatell & Martinez) reported that 18 months after patients switched from a PI regimen to a PI-sparing regimen (abacavir, efavirenz, or nevirapine) body changes did not improve. I suppose you could say that maybe it could take longer than 18 months to improve but the overall study data did not show a trend towards improved lipoatrophy (patients were characterized as having moderate/severe lipoatrophy before switching). Although it wasn't statistically significant there was a trend towards improved fat accumulation in all 3 arms that continued over the course of 18 months in the abacavir & nevirapine arms (here also patients were characterized as having moderate/severe lipoaccumulation).
The purpose of this study was to compare the virologic response when switching protease inhibitors to either nevirapine, efavirenz, or abacavir in patients with <200 copies viral load on 2 nukes and at least 1 PI. This is a randomized, open-label, trial at 15 clinical sites. The primary objective of the study was to examine viral suppression and the secondary objective was to look at the effect of the switch on metabolic measures and body fat abnormalities. Before switching patient characteristics were about the same for all 3 treatment groups: 35% had previously had AIDS, Cd4 was 500, 75% men; most patients had been taking indinavir or nelfinavir with AZT/3TC, d4T/3TC or ddI/d4T. Patients had been on HAART for 30 months (range: 6-53 months). About 50% of the patients in each treatment group had previously taken nukes. And all patients had undetectable viral loads when switching to the new drug. By an intent-to-treat analysis after 18 months, 75% in the nevirapine arm, 69% in the efavirenz arm and 65% in the abacavir arm remained <200 copies. There was no statistical difference between these rates.
This study was initially presented at the Retrovirus Conference in February and this was an update including the new data on body changes. Patients had a higher probability of maintaining virologic control in the nevirapine or efavirenz arms compared with the abacavir arm. However, the rates of viral suppression for patients switching from first-line PI-based regimens were similar for the 3 drugs because the side effect profile for abacavir is easier and perhaps adherence is easier so patients are less likely to discontinue abacavir due to the side effects, adverse events or adherence difficulties.
Patients who switched to abacavir were more likely to experience a viral load failure. After 18 months following the switch 23 patients on abacavir (n=149) experienced a viral load rebound, compared to 7 in the efavirenz group (n=156) and 8 in the nevirapine group (n=155). But the researchers feel this is mostly due to previous exposure and resistance to nukes. Abacavir, however, appears more tolerable. Patients were more likely to experience adverse events on the nevirapine or efavirenz arms compared to the abacavir arms: 10 switched drugs due to adverse events in the abacavir arm compared to 26 in the nevirapine arm & 32 in the efavirenz arm. There were 8 dropouts in the abacavir arm compared to 4 in the nevirapine arm and 7 in the efavirenz arm.
The main adverse events that led to a switch to another drug from efavirenz was neuropsychiatric: 23 of 156 patients; and the most common AE leading to a switch off nevirapine was rash: 13 of 155 patients on nevirapine. 4 patients on nevirapine switched off the drug due to liver toxicity but there were no switches due to this in the EFV or ABC arms. The most common adverse event leading to a switch off abacavir was hypersensitivity to abacavir: 4 of 149 patients.
This was a small study, 30 patients in each treatment group, which I think limits the significance of the results. In each of the 3 groups, TC (total cholesterol)/HDLc (good cholesterol) ratio significantly improved. Triglyceride were reduced significantly only in the NVP group (by 33% from 171 to 114) but were reduced also in the EFV group by 28% from 209 to 143. Triglycerides were 180 at baseline in the abacavir group and 167 at week 48. Total cholesterol improved significantly in the abacavir arm (206 to 187) only, but was reduced in EFV group from 220 to 201 (0.046) and in NVP group from 223 to 207 (NS). HDL (good cholesterol) improved significantly only in the NVP & EFV arms. Insulin trended to improve only in NVP & EFV groups (NS). The proportion of patients with any lipid disturbance at baseline and week 48 were 55% vs 52% in the abacavir arm, 59% vs 54% in the EFV arm, and 67% vs 46% in the NVP arm. NNRTI patients significantly elevated HDLc. In sum, this was a small study, which I think limits interpretation. But NVP appeared to improve triglycerides the most. And all 3 groups appeared to improve total cholesterol although in the NVP group the improvement was not significant.
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