Simon Mallal

Arguably the HIV/AIDS pandemic has presented one of the greatest scientific, humanitarian, and cultural challenges of our time. The Acquired Immunodeficiency Disease Syndrome (AIDS) was first reported in homosexual men in the United States in 1981 and was then seen in hemophiliacs, Haitians, prisoners, and intravenous drug addicts. Slim disease, as it was then called, was recognized shortly afterward in Africa. Intense scientific endeavors resulted in the Human Immunodeficiency Virus (HIV) being identified as the cause of AIDS in 1983. So how did the already marginalized person, their family, and community respond to this mysterious and unpredictable lethal infectious disease? Given enough time and resources, altruism, knowledge, and tools have been able to overcome denial, fear, prejudice, and competing demands. The evolutionary process has provided us a hierarchy of successful and interdependent biologic, cultural, scientific, and medical solutions that have given us the weapons to fight this most formidable biological adversary. Most importantly, our social and altruistic instincts and capacity for rapid cultural adaptation have critically underpinned any scientific or medical success. It is a level at which we can all respond to global challenges.

Abacavir is a nucleoside reverse transcriptase inhibitor used in combination therapy for the treatment of the human immunodeficiency virus type 1 (HIV-1) that has been associated with a hypersensitivity reaction in approximately 8% of those starting the drug. Abacavir hypersensitivity reaction is characterized by greater than or equal to two progressive symptoms typically starting from the second week of therapy (median 9 days) with fever, malaise, nausea, vomiting, diarrhea, and later mild-to-moderate skin rash (present in 70% of patients). Symptoms of abacavir hypersensitivity resolve rapidly with 24 to 72 hours after drug discontinuation. A previous clinical history compatible with abacavir hypersensitivity is a contraindication to future rechallenge as severe morbidity and even mortality characterized by hypotension and shock has been described.

Adverse drug reactions represent a significant burden from a hospital, healthcare and societal perspective comprising the 4th to 6th most common cause of death in some series. Clinically, adverse drug reactions have been classified according to those that are predictable and dose-dependent on the basis of their pharmalogical actions ("Type A") versus those that are believed to be immunogenetically mediated and not predictable based on traditional clinical and pharmalogical properties of the drug ("Type B") (Table 20.1). A major breakthrough has been the association between HLA class I and II alleles and Type B adverse drug reactions. Examples include the striking association between HLA-B*5701 and abacavir hypersensitivity syndrome (ABC HSR), HLA-B*1502 and Stevens-Johnson syndrome/Toxic epidermal necrolysis (SJS/TEN) associated with carbamazepine, and HLA-B*5801 and drug-induced hypersensitivity syndrome (DIHS) and SJS/TEN associated with allopurinol. These associations have been facilitated by the introduction of molecular methods improving the accuracy and resolution of HLA typing and improved phenotyping of specific drug toxicities. Furthermore, the discovery of associations between specific HLA and these drug toxicities such DIHS and SJS/TEN have fuelled our understanding of the immunopathogenesis of these syndromes. The associations between HLA and drug toxicity are hence important from both a clinical and scientific point of view. Drugs may be viewed as an experiment of man acting as a probe to provoke potentially vigorous and life threatening HLA-restricted immune responses. From a clinical standpoint the association between HLA drug toxicity represents an impotant opportunity to increase drug safety and prevent the traditionally unpredictable Type B reactions by excluding high-risk patients from the drug in question. The widespread uptake of HLA-based pharmacogenetics from discovery to clinical implementation.

Abacavir is a guanosine analog that competitively inhibits the reverse transcriptase of the human immunodefiency virus (HIV) and is used in combination antiretroviral therapy for the treatment of HIV. It was approved by the US Food and Drug Administration in 1998 and has been in clinical use since that time. Abacavir is currently most commonly used as part of a fixed-dose combination, 600 mg in combination with lamivudine 300 mg which is given once-daily as part of combination antiretroviral therapy. It is also available as a liquid formulation and has been approved for use in children. Abacavir is well absorbed with an absolute bioavailability of 83% and can be taken without regard to food [1]. Although the parent drug has a short plasma half-life of only 2 h, abacavir is metabolized to carbovir triphosphate which has an intracellular half-life of 20 h or longer [1, 2]. It is this long intracellular half-life of carbovir triphosphate that makes abacavir pharmacokinetically amenable to once-daily dosing and this has been supported by clinical data [3, 4]. Unlike other nucleoside analog reverse transcriptase inhibitors, abacavir is metabolized predominantly by the liver by two major pathways: alcohol dehydrogenase and uridine diphosphate glucruonyltransferase. Less than 2% is excreted unchanged in the urine [1]. In addition, unlike other antiretroviral drugs that are metabolized by the liver such as nonnucleoside reverse transcriptase inhibitors and protease inhibitors, abacavir is not significantly metabolized by cytochrome (CYP) P450 enzymes. It also does not inhibit or induce CYP enzymes which make drug interactions unlikely. Therapeutic drug monitoring has been infrequently employed for abacavir as it is the intracellular concentrations of carbovir triphosphate which would be most likely to be associated with drug effect and these are difficult and costly to measure on a routine basis. There is also very little information on validated intracellular target concentrations and their association with clinical efficacy.

Abacavir is a commonly prescribed HIV drug belonging to the nucleoside reverse transcriptase inhibitor (NRTI) class. The major treatment-limiting side effect associated with its use is an early onset multi-system drug hypersensitivity re-action typically including some combination of rash, fever and gastrointestinal symptoms, occurring within 6 weeks of initiating treatment in approximately 5-8% of abacavir recipients. Susceptibility to this drug hypersensitivity syn-drome is strongly predicted by the presence of a specific human leukocyte antigen (HLA) allele -HLA-B * 5701 -which represents the dominant risk factor for abacavir hypersen-sitivity among Caucasian and Hispanic populations. The frequency distribution of this genetic marker in different populations is likely to provide a rational basis for racially-defined differences in susceptibility, while the critical role of HLA-B * 5701 in directing CD8+ T-cell-dependent, HLA-restricted immune responses provides a key role for this genetic variant in the pathogenesis of abacavir-specific immune responses. In this chapter, we review the implications of this genetic association for clinical practice as well as current knowledge of its immunological basis.