Lipid lowering therapy in patients with HIV infection

CORRESPONDENCE

erythropoietin (EPO), titrating PCV close to 0·50, a limit indicated by the Union Cycliste Internationale. A higher PCV is thought to be harmful. As Gail Davey and Richard Nerurkar point out, little is known about the risks of longterm use of EPO in athletes and of an artificial increase of PCV to 0·50 or more. It is not realistic to extrapolate the risk of thrombotic and other vascular events from patients with atherosclerotic lesions (eg, those with terminal renal insufficiency), to healthy people and certainly not to elite athletes, who are constantly challenging the limits of physiology. A group at risk may be native highlanders, having a physiologically increased PCV. The high PCV is certainly useful at high altitude, but what happens if those athletes train and compete at sea level? And what about altitude training by lowlanders? Fortunately, the effects on PCV of short periods at high altitude were not unimpressive. The often emotional discussion about the manipulation of PCV in athletes is dominated by concern about health risks and fairness in competition. It would be good to stimulate and finance solid scientific investigations on short and long-term hazards of an increased PCV in healthy people and athletes who live at altitude or sea-level. *J J M Marx, P C J Vergouwen *Departments of Internal Medicine and Topsport Medicine, University Medical Centre, PO Box 85500, 3508 GA Utrecht, Netherlands 1

Marx JJM, Vergouwen PCJ. Packed-cell volume in elite athletes. Lancet 1998; 352: 451.

Lipid lowering therapy in patients with HIV infection Sir—Keith Henry and colleagues (Sept 26, p 1031)1 draw many inferences about the value of treatment of hyperlipidaemia in patients with established HIV infection on the basis of only 133 patients and minimum trial data. Although individual cases of accelerated atheroma have been reported2 there are no data on the prevalence of coronary or peripheral arterial disease in this population or its severity. The data for the differences between protease inhibitors are interesting but small scale. The hyperlipidaemias described are mostly mild and the data given insufficient for detailed analysis because HDL or LDL results and the triglyceride range are not provided. National Cholesterol Education Program (NCEP) guidelines were applied to decide treatment but the number of patients that met the different NCEP treatment target criteria are not shown and the

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Drug

Elimination Liver Cytochrome half-life metabolism metabolism (h) (%) Major Minor

Atorvastatin 15–58 Cerivastatin 2–3 Fluvastatin 0·8–1·5 Lovastatin 3 Provastatin 1·3–2·6 Simvastatin 8 Bezafibrate 2 Ciprofibrate 38–86 Fenofibrate 20 Gemfibrozil 6–8

95 70 95 82 50 87 100 100 100 100

3A4 2C8 2C9 3A4 none 3A4 3A4 3A4 3A4 3A4

3A6 3A4 3A4 .. ? various 3A5 .. .. .. ..

1

2

3

4

Fibrates are metabolised in liver, but 70–80% are renally excreted.

Henry K, Melroe H, Huebesch J, Hermundson J, Simpson J, Atorvastatin and gemfibrozil for protease-inhibitor-related lipid abnormalities. Lancet 1998; 352: 1031–32. SoRelle R. Vascular and lipid syndromes in selected HIV-infected patients. Circulation 1998; 9: 829–30. Lennernas H, Fager G. Pharmacodynamics and pharmacokinetics of HMG-coA reductase inhibitors. Clin Pharmacokinet 1997; 32: 403–25. Shepherd J. Fibrates and statins in the treatment of hyperlipidaemia: an appraisal of their efficacy and safety. Eur Heart J 1995; 16: 5–13. Rossen RD. HMG-CoA reductase inhibitors: a new class of anti-inflammatory drugs? J Am Coll Cardiol 1997; 30: 1218–19.

Liver half-lives and cytochrome degradation mechanism for lipid lowering drugs

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applicability of these criteria is dubious in the absence of epidemiological data. The use of fibrates or statins to treat hyperlipidaemia in HIV patients needs to take into account the high prevalence of abnormal liver function tests and possible drug interactions with the multiplicity of medications used in this group. The choice of lipid-lowering drug needs to take into account both drug metabolism and liver metabolism (table) because of possible interactions with the disease and other drugs.3 Most protease inhibitors are metabolised through cytochrome 3A4. Atorvastatin has a long elimination half-life, has active metabolites, and is metabolised through cytochrome 3A4, though interactions seem rare. Provastatin has the least metabolism through cytochromes and has principal renal excretion. Treatment with gemfibrozil has accounted for 90% of the cases of severe myalgia in studies of fibratestatin combination therapy.4 Far more data exist on the use of bezafibrate and fenofibrate in this type of treatment. The consensus amongst lipid specialists favours the use of short half-life statins and fibrates in combination therapy, given at different times, to reduce the possibility of drug interactions. Statins may have unexpected effects in this infection. All statins are antiinflammatory5 and can reduce lymphocyte proliferation or affect macrophage differentiation. Thus they have the potential to increase virus loads or the number of infective relapses in this group of patients. The safety and efficacy of statin or fibrate therapy should be assessed before lipidlowering drugs can be considered for routine primary prevention of coronary heart disease in HIV.

Sir—Keith Henry and co-workers1 highlight the increased risks of coronary atherosclerosis secondary to hyperlipidaemia associated with protease inhibitors. They report that patients receiving ritonavir and saquinavir are most likely to develop this complication. Of more immediate concern, is the risk of pancreatitis secondary to these lipid abnormalities. We describe a case of pancreatitis and pseudocyst formation in a patient receiving ritonavir and saquinavir. A 48-year-old man, found to be HIV seropositive in 1994 after an episode of acute pneumocystis pneumonia (PCP), was started on zidovudine, didanosine, and secondary PCP prophylaxis. In 1995, disseminated Mycobacterium avium-intracellulare infection was diagnosed. He was treated with rifabutin, stavudine, and indinavir. Because of peripheral neuropathy, his nucleoside reverse-transcriptase inhibitors were stopped and he was started on saquinavir 600 mg and ritonavir 600 mg twice daily. 4 months later, he was admitted with a 3-day history of severe upper abdominal pain and nausea. There was no history of alcohol intake or gallstones. On examination, there was upper abdominal tenderness and guarding. His amylase was raised (246 ␮mol/L), and liver enzymes were high (alkaline phosphatase 345 IU/L, aspartate aminotransferase 102 IU/L, ␥-glutamyl transferase 485 IU/L). An ultrasound and computed tomography (CT) scan showed a well-demarcated low attenuation cyst within the head of the pancreas (2⫻3 cm). There was no pancreatic calcification, gallstones or focal hepatic parenchymal changes. There was no evidence of hepatic-duct dilation or sclerosing cholangitis on endoscopic retrograde cholangiopancreatography. Protease inhibitors were discontinued and he was managed with analgesia and parenteral nutrition. A follow-up CT scan 3 weeks later showed complete involution of the cyst.

*Anthony S Wierzbicki, Timothy M Reynolds, Martin A Crook, Joanna Tatler, Barry S Peters Departments of *Chemical Pathology, Genitourinary Medicine, and Pharmacy, St Thomas’ Hospital, London SE1 7EH, UK; Burton Hospitals, Burton-on-Trent, Staffordshire

THE LANCET • Vol 352 • November 28, 1998