AIDSWEEKLY Plus; Monday, August 10 & 17, 1998
Daniel J. DeNoon, Senior Editor

The hypothesis explains the various disfiguring side effects (distended abdomen, buffalo hump on the back of the neck, enlarged breasts in women, wasting in the face and limbs) and metabolic events (diabetes, increased bleeding in hemophiliacs, hyperlipidemia) reported by patients receiving protease inhibitors as part of highly active antiretroviral therapy (HAART).

These disturbing side effects may lead physicians to avoid the use of PIs in asymptomatic patients. For symptomatic patients, the drug toxicities are not nearly as devastating as HIV disease.

"There is no question that the risk/benefit favors PIs in symptomatic/poor prognosis disease," said David A. Cooper of the University of New South Wales, Sydney Australia. "In asymptomatic infection the benefit is not known and protease-sparing regimens should be considered."

Cooper described his hypothesis in an address to the 12th World AIDS Conference, held June 28-July 3, 1998, in Geneva, Switzerland.

In one series of patients, incidence of lipodystrophy was 50 percent after 10 months of treatment with PIs. All currently approved PIs appear to be associated with the syndrome, although Abbott's ritonavir seems disproportionately represented. Cooper made an urgent plea for more study of the phenomenon.

"We are doing a lot of opinion-based medicine," he said. "We need clinical trials."

In their effort to find the basis for PI-associated lipodystrophy Cooper's research team noted that PIs have been considered HIV specific because they do not affect human aspartyl proteases. But developers of the drugs did not search human genomic databases for homology with human proteins.

When Cooper et al. did this, they found that the catalytic side of HIV-1 protease has 60 percent homology to two human regulatory proteins that affect lipid metabolism: cytoplasmic retinoic-acid binding protein type 1 (CRABP-1) and low density lipoprotein-receptor- related protein (LRP).

Inhibition of CRABP-1 would impair metabolism of retinoic acid, leading to fat-cell death and consequent lipid release and/or reduced lipid storage.

Inhibition of LRP would result in failure to remove fatty acids from circulating triglycerides in the vascular endothelium and to reduced chylomicrons in the liver.

These mechanisms are associated with inhibition of the liver enzyme cytochrome P450 3A. As ritonavir is the most potent cytochrome P450 3A inhibitor of all the PIs, the hypothesis would explain why lipodystrophy appears worse in ritonavir recipients.

Cooper noted that the lipodystrophy syndrome has two components: peripheral fat wasting and central adiposity. He presented the case history of a man with extreme loss of facial fat, loss of fat at the neck and arms, and a distended abdomen.

Other symptoms possibly associated with PI lipodystrophy include increased bleeding and factor VIII requirements in hemophiliacs, ectodermal dysplasia (manifested as dry skin, cracked lips, ingrown toenails, and body alopecia), premature coronary artery disease, and gynecomastia. Cooper said that pancreatitis would be expected, but has not yet been documented.

In his call for more research Cooper spelled out his agenda: development of a consensus case definition, validation of his hypothesis regarding CRABP-1 and LRP, gathering of more data from women and children, clarification of whether only PIs cause the syndrome, identification of predictors of the syndrome, investigation into whether the syndrome is reversible, study of vascular complications, and exploration of treatment (e.g., diet or lipid- lowering drugs).

Cooper also called for caution before changing patients' HAART regimens.

"I'm very reluctant to switch anybody at the present time, especially previously symptomatic patients," he said. "It's important to know whether one PI affects a particular target more than another. It's a class-specific phenomenon, but there may be individual differences."

Finally, the Australian researcher called for drug developers to screen potential new HIV protease inhibitors for effects on human proteins identified via database searchers.

Cooper and colleagues recently published their hypothesis in the journal The Lancet ("Pathogenesis of HIV-1-Protease Inhibitor- Associated Peripheral Lipodystrophy, Hyperlipidemia, and Insulin Resistance," Andrew Carr et al., Lancet, 1998;351:1881-3).

The corresponding author for this study is Andrew Carr, HIV Medicine Unit, St. Vincent's Hospital, Sydney, 2010 Australia. Email: <acarr@stvincents.com.au>.

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