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Body Changes: indinavir vs nevirapine vs 3TC, plus d4T/ddI. Protease Inhibitors Appear to Increase Risk For Premature Heart Disease
Reported by Jules Levin
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In the FRAMS II Atlantic Sub-Study treatment-naive patients received either indinavir, nevirapine, or 3TC in combination with ddI/d4T. So, everyone in the study received ddI plus d4T and then patients were randomized to either indinavir (Crixivan), nevirapine (Viramune), or 3TC (a triple nuke regimen). This sub-study is relatively small (about 15-20 patients in each treatment group). Rob Murphy from Northwestern & the ACTG reported what I think are important findings.
--After 144 weeks of therapy (3 years), Murphy's findings suggest that patients receiving indinavir had more fat accumulation in the belly than the 3TC regimen and the nevirapine regimen (IDV vs NVP: p=.0007; IDV vs 3TC: p=.002). But on average patients on 3TC or NVP could also experience some fat accumulation.
--Interestingly, Murphy also found that fat loss (lipoatrophy) was no different in the 3 arms at week 144 and over time, bear in mind all three treatment groups were taking ddI + d4T.
--Thirdly, Murphy found that after 72 weeks of therapy 49% reported lipoatrophy (24% moderately severe) and 25% reported fat accumulation (13% moderately severe).
--A fourth important finding was that good cholesterol (HDL) increased in the patients receiving nevirapine but remained the same for the patients receiving 3TC or indinavir. Although we're not sure what this means, it is probably good when HDL increases.
David Wohl, MD, UNC, a lipodystrophy researcher, is covering lipodystrophy and metabolics at this conference for NATAP, and his analysis and coverage will be available soon.
Murphy listed the study limitations: the study was small; the fact that all patients received ddI/d4T precluded a comparison with other double nuke regimens; it's hard to sort out the effects of HIV disease and immune reconstitution from HAART on the study findings. The changing of antiretrovirals by the patients during the study may have had some effect. And, the study analysis is cross-sectional and there were no baseline measures. Murphy recommended further study to clarify his findings. Still, I think the findings have some significance.
The FRAMS study is a sub-study of the Atlantic Study which randomized 298 treatment-naive patients with >200 CD4s to one of the 3 regimens (IDV 800 mg three times per day, NVP 400 mg once daily, 3TC 150 mg twice daily) plus d4T/ddI. About 80% were female, average age 35, 55% MSM, 19-27% heterosexual, 13-19% IVDU, average CD4 count was 400 and viral load 4.3 log (about 20,000). Patients were followed for 5 years on average in this study, that's a relatively long follow-up. There were 15 patients in the IDV sub-study, 17 in the NVP arm, and 20 in the 3TC arm, so the sub-study is relatively small.
After 96 weeks of therapy 50% in the IDV arm, 59% in the NVP arm, and 45% in the 3TC arm had <500 copies/ml (ITT analysis). These data were presented in more detail previously, and these data are not the point of this lipodystrophy sub-study.
More patients in the indinavir arm (7) discontinued their study drug than in the NVP (4) or 3TC arm (2). All 3 groups were equally exposed to the ddI and d4T backbone. At week 144, patients on average had increased CD4s from 360 to 560-650. And viral load decreased on average from 4.3 log to <2.7 log. Patients had about 200 weeks on ddI and d4T.
Cholesterol
Body changes were evaluated by questionaire completed by doctor, and correlated with DEXA results. Good cholesterol (HDL) increased in the nevirapine arm by about 50% from the time of beginning study therapy to week 96. But good cholesterol (HDL) remained about the same over the 96 week period for the patients in both the 3TC & indinavir groups.
At week 72, 49% of patients had mild to severe fat loss (face, legs, arms, buttocks), and 24% had moderate to severe fat loss. 25% had fat accumulation (abdomen, neck, breasts) and 13% had moderate to severe fat accumulation. 10% had both fat loss and accumulation. There was no significant difference noted between the treatment groups.
52 patients had mid-abdomen CT-scans: 12 patients had only 1 scan, 13 had 2 scans, 27 had 3+ scans. In total 158 scans were performed; on average 3 per patient. At 144 weeks, average visceral adipose tissue (fat accumulation in the belly) was 171 cm2 in the 15 IDV patients compared to 85 in the 16 NVP arm and 90 in the 18 3TC arm, these differences were statistically significant. The subcutaneous fat (measure of fat loss) was 126 cm2 in IDV patients, 94 in the NVP group, and 82 in the 3TC patients, but the differences were not statistically significant. So, this suggests there was no difference in fat loss between the 3 treatment groups. Some patients on NVP did experience some increase in fat accumulation and some patients on NVP did not. And the same occurred for the patients on 3TC.
Lastly, I'd like to review again the brief report I filed to you yesterday about the relationship between PI use and premature heart disease. A rather large Italian study was reported yesterday in the same afternoon oral session in which the FRAMS study was reported. The researcher found that patients receiving PI therapy were more likely to experience premature heart disease than patients receiving NNRTI therapy. Bear in mind that 87% of the study patients were cigarette smokers which is likely to accelerate onset of an event. The study found by about 20 months on therapy (lag time) patients started to experience an event and by 42 months of follow-up there were 23 events in the PI arm vs 2 in the NNRTI arm. This study appeared to create quite a stir and much discussion among doctors here. The study found patients with elevated lipids were more likely to experience an event and patients with lipodystrophy were more likely to experience an event. It's important to bear in mind that since these patients had a key risk factor, cigarette smoking, this played a key role in accelerated progression. And patients without such a risk factor are not likely to experience heart disease for a number of additional years. There has been much discussion and controversy about the risk that elevated lipids in HIV would result in increased risk for prmature heart disease as it does in HIV-negative individuals. These study results provide further evidence that elevated lipids in HIV can lead to increased risk for heart disease. Also important, after the presentation by the Italian researcher, he said in private discussion that the events occurred for these patients when they were <48 years of age and on average about 35 years, a young age.
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