INTRODUCTION: OVERVIEW OF COMPLICATIONS ASSOCIATED WITH HIV THERAPY
Over the past decade there has been a dramatic transformation in the management of human immunodeficiency virus (HIV) infection — one that has brought about an increased focus on the adverse effects of antireroviral therapy.
Although antiretroviral drugs were available in clinical practice from approximately 1987 onward with the introduction of zidovudine (ZDV, also known as azidothymidine or AZT), HIV therapy was initially characterized by the rapid development of drug resistance in patients receiving treatment. This meant that after a period of adequate response to treatment generally lasting several months, the inevitable development of drug resistance meant that patients again experienced an inexorable decline in immunologic status due to a high burden of productive viral infection, becoming susceptible to opportunistic infections and other acquired immunodeficiency syndrome (AIDS)-defining illnesses that were associated with considerable morbidity and, eventually, mortality. However, this era came to an end in approximately 1996, with the introduction of combination treatment regimens (commonly referred to as “highly active antiretroviral therapy” [HAART]) that were capable of profoundly suppressing HIV replication for prolonged periods, thereby reducing the risk of drug resistance and also halting and subsequently reversing the effects of the virus on immune function in infected patients. Accordingly, there are profound prognostic benefits associated with HAART that are now well documented in observational cohort studies.1-3However, although the use of HAART regimens for HIV-infected patients has fundamentally altered the prognosis of this disease, this relatively new paradigm in which HIV infection can be viewed as a chronic, manageable disease has also increased awareness that long-term drug toxicities have the potential to cause significant morbidity and even mortality in this patient population. Recent analyses suggest that the burden of serious drug toxicities (that is, grade 4 reactions) remains greater than the risk of disease-associated complications, even in patients with advanced immune deficiency and AIDS.4,5 To some extent, this simply provides further testimony to the beneficial diseasemodifying effects of HAART, although these results also indicate that clinicians and patients alike need to be conscious of drug toxicity as a possible cause of any symptoms during (lifelong) therapy.
There are many potential complications associated with antiretroviral drug use, reflecting the great variety of HIV drugs that are available and widely used in clinical practice. The potential role of apoptosis in the pathogenesis of these adverse events will be the subject of this chapter, which will also develop the theme that each individual drug has a specific toxicity profile (even with drug classes, as will be discussed), so that both clinical management and scientific research need to be guided by this principle. The discussion will commence with the drug class in longest use for the treatment of HIV infection, the nucleoside analogue reverse transcriptase inhibitors (NRTIs), taking examples of toxicity syndromes that highlight underlying mechanisms, and will then move on to examine the complications associated more strongly with HIV protease inhibitor (PI) drug therapy.