Toxicity of antiretroviral therapy and implications for drug development

Abstract

The toxicity of antiretroviral therapy is an increasingly important issue in the management of patients with human immunodeficiency virus (HIV). With sustained major declines in opportunistic complications, HIV infection is increasingly a more chronic disease, and so more drugs are being used in more patients for longer periods. However, permanent and near-perfect adherence to antiretroviral therapy is needed to maximize its long-term benefits. Although adverse reactions to antiretroviral therapy are common, and profoundly affect its clinical efficacy by limiting adherence, many such reactions are poorly studied and analysed, and are under-reported. This article summarizes adverse events associated with antiretroviral therapy, and discusses weaknesses and possible solutions in the study, analysis and reporting of adverse events that could improve antiretroviral drug development.

Key Points

  • Morbidity and mortality due to infection with HIV have been considerably reduced since the introduction of highly active antiretroviral therapy (HAART) — combinations of at least three antiretroviral drugs — in the late 1990s.

  • Although HAART regimens have considerable antiretroviral activity, the durability of viral suppression is often limited for several reasons, including drug toxicity, which can compromise the near-perfect adherence that is needed to maintain the efficacy of HAART.

  • The main toxicities — which include mitochondrial toxicity, hypersensitivity, lipodystrophy, dyslipidaemia and type 2 diabetes — are described here.

  • However, despite their impact on drug adherence, toxicities due to antiretroviral therapy have been poorly studied, analysed and reported.

  • Addressing these deficiencies should lead to safer and more effective long-term use of antiretroviral therapy (and so to reduced morbidity and mortality), particularly in special patient populations, and to better drug development.

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Figure 1: Hepatic steatosis secondary to nucleoside analogue therapy.
Figure 2: Clinical features of HIV lipodystrophy.
Figure 3: Pathogenesis of HIV lipodystrophy, dyslipidaemia and insulin resistance.
Figure 4: Cutaneous drug hypersensitivity.

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Online Table 1 | Known and probable mitochondrial toxicities of NRTIs /NtRTIs (PDF 18 kb)

Online Table 2 | Dealing with the metabolic complications of HIV and HAART (PDF 17 kb)

Online Table 3 | Antiretroviral hypersensitivity (PDF 15 kb)

Online Table 4 | Liver dysfunction associated with antiretroviral therapy (PDF 23 kb)

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DATABASE

LocusLink

GLUT-4

HIV-RT

PPAR-γ

RXR

SREBP-1

FURTHER INFORMATION

Encyclopedia of Life Sciences

HIV life cycle and inherited co-receptors

human immunodeficiency virus

CONSORT statement

International Committee of Medical Journal Editors

International Conference on Harmonisation

Lipodystrophy scoring system

Glossary

PERIPHERAL LIPOATROPHY

Diffuse loss of subcutaneous/peripheral fat without loss of lean body mass or visceral fat.

LIPOMATOSIS

Focal fat accumulation.

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