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  3rd International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV
Athens, Greece - October 2001
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Nevaripine: lipids and heart disease; hepatotoxicity and a role for therapeutic drug monitoring
  At Athens and at previous conferences it has been reported from studies that abacavir triple nuke and NNRTI regimens appear to have better profiles in terms of lipid (fats- cholesterol, triglycerides) changes compared to PI regimens. Previously reported studies have suggested that perhaps the better lipid profiles are associated with nevirapine and abacavir regimens. Studies looking at efavirenz have showed less consistent results in comparison to NVP and abacavir studies. Although good cholesterol improvement appears associated with efavirenz. Often, when lipids show improvements in studies they do not return to normal. This type of information has important implications for the potential risk of heart disease facing HIV-infected patients. On the other hand efavirenz appears to perform better in viral suppression compared to nevirapine and abacavir. Still, studies switching patients from a PI to a PI sparing regimen has not been shown to improve fat redistribution in general.
One problem with these types of studies on lipids and glucose is that often the results vary from one study to another. Although at times the results are duplicated from one study to the next, at times the results are different. For example, one abacavir study may show an improvement in glucose while another may not. This variation in results may be due to study design differences such as whether blood testing was fasting and the backgrounds of the patients. Since the studies are often small if more patients in one arm have bad diet or genetic predisposition to elevated lipids or diabetes that may effect the study outcome. I think, often doctors are left to make treatment decisions based on their experience in treating patients and their judgement, with guidance from these studies.
At Athens there was a key and interesting presentation by Vincent Mooser on elevated lipids and the risk for heart disease that patients may face. Previously reported studies have reached similar conclusions that there is a clear increased risk for heart disease. Generally, it takes years for heart disease to develop. So for most people there is a low risk for heart disease in the next several years. But as years mount up, perhaps after 7-10 years or longer the risk may be more increased compared to healthy non HIV-infected patients. But the risk may be comparable to HIV negative persons with similar risk factors: high cholesterol and trglycerides, high sugar and diabetes. One key point Mooser made was the presence of risk factors in persons with HIV. For example, he pointed out, as was also pointed out at last year's Lipodysttrophy Workshop, that cigarette smoking, genetic predisposition, diet, and not exercising are risk factors for heart disease that appear to occur often in people with HIV. If a patient has these risk factors elevated fats and sugar may increase their risk for premature heart disease. Mooser also identified age as a key risk factor. So, as we get older HIV-infected people face increasing risks. The presence of a pot-belly is a risk factor for heart disease and we know that fat accumulation in the belly is part of the fat redistribution syndrome. At Athens and previously we have seen data associating indinavir and perhaps other protease inhibitors with elevated sugar and the potential for insulin resistance. Although it has been reported from studies that switching a patient from a PI regimen to a PI sparing regimen (abacavir triple nukes, efavirenz and nevirapine based regimens) can improve the overall lipid profile, it is important to bear in mind that switching a regimen can risk control of HIV suppression. In particular, if a patient has nuke resistance perhaps from a prior regimen virologic failure is a risk after the switch due to the pre-exsiting resistance. If a person has nuke resistance switching to an abacavir triple nuke regimen entails perhaps greater risk for viral failure. However, after following switch studies for almost two years there is no evidence that fat redistribution reverses.
The Atlantic Study: 96-week metabolics data
At Athens, M van der Valk reported a 96 week update from the previously reported 48 weeks data on lipid changes in 3 regimens followed in the Atlantic Study. The Atlantic Study is an ongoing, randomized, open-label study with 3 arms and comparing nevirapine, indinavir and 3TC arms all in combination with ddI+d4T. Standard dosing was used except nevirapine and ddI were dosed once daily. Patients were treatment-na´ve. Fasting was not mandatory for blood draws.
The researchers conducted the Fat Redistribution and Metabolic Sub-study (FRAMS) to explore differences between the arms in metabolics. However, the study does not appear to compare changes in fat redistribution. 139 of the total enrolled 298 patients in this study remained on randomized treatment for 96 weeks. Researchers evaluated 98 patients of the 298 who remained enrolled in the Atlantic Study for at least 96 weeks and who had HDL-cholesterol values available from both week 0 and 96. Patients were included in this analysis if they remained on randomized treatment for 96 weeks.
Van de Valk reported at Athens that previously the Atlantic Study researchers reported 24-week data, which found a 49% increase in HDL-cholesterol (good cholesterol) in patients receiving nevirapine. And increases in Apolipoprotein (19%), lipoproteinAl (38%), and HDL particle size (3%) in these patients. The present study analysis was to examine the longer-term lipid profiles after 96 weeks.
Van der Valk reported that patients receiving the nevirapine regimen (n=32) experienced a 40% increase in good cholesterol at week 96 compared to their baseline value. Patients receiving indinavir (n=28) had a 6% increase and patients receiving the 3TC arm (n=38) had a 20% increase (NVP > IDV p<0.001). Baseline HDL cholesterol was 0.99 mmol/L for patients taking indinavir, 0.95 for NVP, and 0.83 for 3TC. Study investigators reported the most frequently observed adverse events related to nevirapine treatment were rash, nausea, diarrhea, and fatigue.
Triglycerides increased 96% for patients receiving indinavir compared to 46% for patients taking nevirapine and 61% for those taking the 3TC regimen (p<0.001). LDL-cholesterol (bad cholesterol) increased 14% for patients taking indinavir, 19% for patients taking NVP, and 3% for 3TC. These changes were not statistically significant. The total:HDL cholesterol ratio decreased 6% compared to an increase of 25% for indinavir (nvp > IDV, p=0.006). But for 3TC the total:HDL cholesterol ratio increased 2%. However, B Clotet reported at the 8th European AIDS Conference this week that LDL cholesterol and triglycerides fell for patients taking the nevirapine regimine in a small open-label study of patients who were on a PI regimen (n=26) and were randomized to either remain on PI therapy or switch to efavirenz (n=25) or nevirapine (n=26).
Liver Toxicity and Therapeutic Drug Monitoring
At Athens, Vincent Soriano reported on a study (n=70) finding higher nevirapine blood levels are associated with liver toxicity. In those patients with elevated ALT, NVP levels (mean ug/ml) were 6.2 while patients with no ALT elevation had a mean NVP level of 5.2 (p=0.02). Soriano suggested that the risk of liver toxicity in patients with chronic HCV treated with NVP may in part be due to an increase in NVP blood levels as a result of reduced metabolism of the drug. It was suggested at the workshop that other drugs may yield similar results if studied. However, he said that perhaps only more advanced liver disease presents such a situation where metabolism is inhibited to such an extent as to result in clinically significant higher drug levels. To that point, he showed data that is not statistically significant suggesting that HCV coinfection itself does not enhance NVP plasma levels, a phenomenon which might be restricted to subjects with end-stage liver disease. HCV positive patients (n=32) had NVP levels of 5.8 ug/ml (range 0.7-9.1) compared to HCV negative patients (n=38) with NVP levels of 6.1 ug.ml (range 0.9-9.6). But, this subject has not received much research attention. Perhaps middle stage liver disease raises HIV drug levels and leads to liver toxicity, but this has not been researched much. This could be a situation where therapeutic drug monitoring may be used to evaluate drug blood levels for coinfected patients for the HIV medications they are taking. Soriano also reported having HCV was associated with elevated ALT, as 23 patients who had elevated ALT had HCV in the study compared to 9 who had HCV but did not experience elevated ALT (p=0.003).