Publications

With advances in antiretroviral therapy, many HIV+ individuals are living longer lives and some are developing end-stage renal and/or hepatic disease requiring transplantation. These patients require concomitant use of immunosuppressants (e.g., cyclosporine [CsA]) and antiretrovirals (e.g., protease inhibitors [PIs]), which exhibit narrow therapeutic windows and are substrates and inhibitors of cytochrome P450 3A enzymes and the cellular transporter P-glycoprotein. In this pilot study, HIV+ subjects on either oral nelfinavir (NFV) or indinavir (IND) with nondetectable viral loads and normal renal and hepatic function had 12 hour pharmacokinetic (PK) studies on 3 separate days: PIs alone, PIs+intravenous CsA, and PIs+oral CsA to determine the extent of PK interactions between these medications. PIs and CsA concentrations were measured by LC/MS in plasma and whole blood, respectively. Nine subjects (n=7 on NFV, n=2 on IND) completed the study. Only the results of those subjects taking NFV are reported. Oral co-administration of CsA increased NFV T(max) from 2.6+/-0.9 to 3.2+/-0.8 h (p<0.05), and AUC(0-infinity) from 27.9+/-15.2 to 43.2+/-27.1 mg(*)h/mL (p=0.06). Intravenous CsA did not appreciably alter oral pharmacokinetics of NFV. Both CsA and NFV PK parameters exhibited a high degree of intersubject variability, underscoring the need for routine therapeutic drug monitoring of both CsA and PIs in HIV+ subjects undergoing transplantation.

With the introduction of combination antiretroviral therapy, changes in fat distribution and serum metabolites were reported. These included increased central fat ("buffalo hump," abdominal, and visceral); decreased peripheral fat (in the face, legs, and arms); increased levels of triglycerides, low-density lipoprotein and total cholesterol, glucose, and insulin; and low levels of high-density lipoprotein cholesterol. Many of these changes predict increased atherosclerosis. It has been proposed that these findings are part of a single syndrome, much like metabolic syndrome. Our data indicate that many of these changes are independent. Some changes are antiretroviral drug (but not necessarily class)-specific, some represent the restoration to health, and others are due to effects of the host response to human immunodeficiency virus itself.