Last update:
28-Jul-2000

Arch Hellen Med, 16(5), September-October 1999, 437-551

REVIEW

The long-term toxicity of potent antiretroviral treatment

Η. SAMBATAKOU, P. GARGALIANOS
Special Infections Unit, General Hospital of Athens "G. Gennimatas", Athens, Greece

Recent advances in the treatment of HIV infection after the introduction of protease inhibitors (PIs) as part of potent antiretroviral therapy (PAT) have dramatically changed the natural history of HIV infection, leading to a reduction of death rates worldwide. However there is an increasing recognition and concern for adverse events (AEs) following long-term exposure to PAT. With today's increasing survival rates, it is obvious that nucleoside analogues (NsRTIs) have a long-term toxicity profile which is well described in vitro and in vivo. The underlying mechanism of such toxicity is a reduction of mitochondrial oxidative phosphorylation. The non nucleosides analogues (NNsRTIs) and the new NsRTI abacavir are characterized by a generalized hypersensitivity reaction which occurs in a relatively high proportion of patients and is the most common reason for discontinuation of therapy. An unexpected syndrome consisting of changes in body shape due to redistribution of body fat and metabolic alterations has been recently reported with increased frequency in HIV-1 infected patients who are otherwise responding well to therapy. This is widely believed to be a side effect of PI therapy, although a causal relationship has not been established. The most obvious changes in body shape are truncal obesity and thinning of the extremities, often with prominence of the veins. Facial changes, an increased dorsocervical fat pad (buffalo hump) and breast enlargement in women have also been noted. Although metabolic abnormalities have been described in HIV infection regardless of therapy, the pattern of metabolic disorders in patients on PI therapy is different, including hyperlipidemia, insulin resistance and more rarely new-onset diabetes mellitus, hypogonadism or gout. Although homology of the catalytic region of the HIV protease enzyme to regions within two proteins which regulate lipid metabolism has led to the hypothesis that the syndrome is caused by inhibition of these enzymes by PIs, there are reports of patients with elements of this syndrome who have never received PIs. The case definition, precise incidence, relationship with antiretroviral therapy, the pathogenesis, management, probability of reversal and the long-term consequences of this syndrome, such as cardiovascular disease, are areas for further investigation.

Key words: Adverse reactions, Antiretroviral treatment, HIV-infection, Lipodystrophy.