Page 37 - HIV/AIDS Guidelines

viruses. In vitro, the assay can detect CXCR4-utilizing clones with 100% sensitivity when those clones make
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up 0.3% of the population. Although this more sensitive assay has had limited use in prospective clinical
trials, it is now the only one that is commercially available. For unclear reasons, a minority of samples
cannot be successfully phenotyped with either generation of the Trofile assay. In patients with plasma HIV-1
RNA below the limit of detection, coreceptor usage can be determined from proviral DNA obtained from
peripheral blood mononuclear cells; however, the clinical utility of this assay remains to be determined. 11

Genotypic Assays

Genotypic determination of HIV-1 coreceptor usage is based on sequencing the V3-coding region of HIV-1
env, the principal determinant of coreceptor usage. A variety of algorithms and bioinformatics programs can
be used to predict coreceptor usage from the V3 sequence. When compared to the phenotypic assay,
genotypic methods show high specificity (~90%) but only modest sensitivity (~50%–70%) for the presence
of a CXCR4-utilizing virus. Given these performance characteristics, these assays may not be sufficiently
robust to completely rule out the presence of an X4 or D/M variant. 12

Recent studies in which V3 genotyping was performed on samples from patients screening for clinical trials
of MVC suggest that genotyping performed as well as phenotyping in predicting the response to MVC. 13-14
On the basis of these data, accessibility, and cost, European guidelines currently favor genotypic testing for
determining coreceptor usage. An important caveat to these results is that the majority of patients who
received MVC were first shown to have R5 virus by a phenotypic assay (Trofile). Consequently, the
opportunity to assess treatment response to MVC in patients whose virus was considered R5 by genotype but
D/M or X4 by phenotype was limited to a relatively small number of patients. It is also important to note that
the genotyping approaches used in these studies are not routinely available from clinical laboratories in the
United States at this time.

Given the uncertainty regarding the genotypic assays and fewer logistical barriers to obtaining a phenotype
in the United States than elsewhere, the Panel recommends that a phenotype be used as the preferred
coreceptor tropism screening test in the United States.

Use of Coreceptor Tropism Assays in Clinical Practice

Coreceptor tropism assays should be used whenever the use of a CCR5 inhibitor is being considered (AI).
Coreceptor tropism testing might also be considered for patients who exhibit virologic failure on MVC (or
any CCR5 inhibitor) (CIII).

Other potential clinical uses for the tropism assay are for prognostic purposes or for assessment of tropism
prior to starting antiretroviral therapy (ART), in case a CCR5 inhibitor is required later (e.g., in a regimen
change for toxicity). Currently, sufficient data do not exist to support these uses.

References

1. Moore JP, Kitchen SG, Pugach P, et al. The CCR5 and CXCR4 coreceptors--central to understanding the transmission
and pathogenesis of human immunodeficiency virus type 1 infection. AIDS Res Hum Retroviruses. 2004;20(1):111-126.
2. Fatkenheuer G, Pozniak AL, Johnson MA, et al. Efficacy of short-term monotherapy with maraviroc, a new CCR5
antagonist, in patients infected with HIV-1. Nat Med. 2005;11(11):1170-1172.
3. Connor RI, Sheridan KE, Ceradini D, et al. Change in coreceptor use correlates with disease progression in HIV-1--
infected individuals. J Exp Med. 1997;185(4):621-628.
4. Koot M, Keet IP, Vos AH, et al. Prognostic value of HIV-1 syncytium-inducing phenotype for rate of CD4+ cell
depletion and progression to AIDS. Ann Intern Med. 1993;118(9):681-688.
5. Hunt PW, Harrigan PR, Huang W, et al. Prevalence of CXCR4 tropism among antiretroviral-treated HIV-1-infected

Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents C-19

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