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diseases like RA, the benefit:risk ratio can considered to be intermediate between these two
extremes. The reason is that monoclonal antibodies against tumor necrosis factor have proven
to be very efficacious and have become the standard of care. Despite their obvious success these
therapeutics provide clinically significant benefit in only up to 50-60% of patients leaving a sig-
nificant proportion of the RA population underserved [70] . Moreover, anti-TNFs are associated
with serious ADRs including malignancy and tuberculosis. Another interesting example is pro-
vided by anti-retrovirals that are used to control the human immunodeficiency virus (HIV). Up
to the mid-1990s when HIV and the ensuing AIDS were often fatal, significant ADRs caused by
anti-retrovirals were considered acceptable because those drugs were the only proven means
of controlling HIV. With the introduction of anti-retroviral cocktails, HIV has become a chronic
and manageable condition in Western countries which in turn has significantly improved the
benefit:risk ratio, thus resulting in less acceptance of ADRs for new anti-HIV medications.
Previous sections of this chapter described proactive translational strategies to identify
patients more likely to benefit from a therapeutic. It is challenging, however, to employ such
approaches to ADRs because they are treatment-emergent and usually unpredictable. We
describe below two genomic approaches that have been used to understand the mechanism
of an ADR. This mechanistic knowledge has been applied to develop a test to screen for
patients susceptible to ADR caused by the anti-retroviral abacavir or to develop follow-on
compounds to muraglitazar, an investigational anti-diabetic.
1.4.1 Case Study: Abacavir in HIV
Abacavir (ABC) is a nucleotide analogue that competitively inhibits HIV reverse tran-
scriptase. ABC can be associated with an ADR characterized by fever, malaise, gastrointes-
tinal symptoms and internal organ involvement in approximately 5-8% of patients who
begin therapy with the drug [71] . The syndrome can be accompanied by a mild-to-moderate
rash in 70% of patients with ABC hypersensitivity and is associated with severe hypoten-
sion and possible death upon re-challenge, in contrast to the complete resolution of symp-
toms 72 hours after withdrawal of the drug [72] .
Two groups independently performed a case-control genetic association study between
HLA alleles and susceptibility to ABC-induced hypersensitivity and found highly significant
association with the HLA Class I allele, HLA-B*5701 [73,74] . These studies demonstrate better
than any simulation that when the genetic effect size is substantial (odds ratios for the associ-
ated allele were 24 and 103) even relatively small case-control studies - DNA from 18 and 85
cases of ABC-induced hypersensitivity was evaluated in the two studies - can provide useful
information. These initial reports were confirmed by several other groups and led to a prospec-
tive trial to test whether screening for HLA-B*5701 could reduce the incidence of ABC-induced
hypersensitivity. PREDICT-1 was a large (N = 1956) double-blind study that randomized
patients to either receive real-time HLA-B*5701 screening and exclusion of ABC for those posi-
tive for HLA-B*5701 or ABC initiation and clinical monitoring with retrospective HLA-B*5701
analysis [75] . The study demonstrated that HLA-B*5701 had 100% sensitivity and 97% speci-
ficity for ABC HSR and a negative predictive value of 100% and a positive predictive value of
47%; i.e., not only are patients without the HLA-B*5701 allele highly unlikely to develop ABC-
induced hypersensitivity, but about half those who carry the HLA-B*5701 are also unlikely to
develop this ADR. A case-control study extended these findings from a study that enrolled
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