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Virologic Outcome After geno2pheno Versus Trofile: Controversy on Using Genotype to Predict Coreceptor Use Before Maraviroc
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7th European HIV Drug Resistance Workshop, March 25-27, 2009, Stockholm
Mark Mascolini
After 12 weeks of treatment with a maraviroc-containing rescue regimen, patients screened for coreceptor use by the genotype-based geno2pheno method had virologic results equivalent to those screened with the Trofile phenotypic assay [1]. Positive predictive value for virologic response was similar with the two tests. A separate study in a different patient group found excellent correlation between coreceptor determinations with geno2pheno and the enhanced Trofile assay [2]. (from Jules: there have been many studies conducted to date and reported at conferences on using genotypic assays for tropism, but to date none of the studies has provided adequate support with data that any genotypic assay or any other potential tropism assay can provide reliable information equal to that provided by the Enhanced Trofile Assay, and the Enhanced Trofile Assay is the only assay both the FDA and Pfizer support. As you can see below several key researchers agree that genotyping for tropism has not established itself as a reliable assay. My understanding is that some commercial labs are providing to clinicians other tropism assays besides the enhanced Trofile assay without informing clinicians that the other assay has not been properly vetted and qualified, and this is very questionable behavior by the labs, and not good for patients.
Still, the original Trofile assay remains the only coreceptor predictor validated in clinical trials (the maraviroc MOTIVATE studies), and some leading investigators argue--strenuously--that genotyping requires closer scrutiny, and better sensitivity, before clinicians can reliably use it in practice. The temptation to use genotyping is great because it is much faster and cheaper than phenotyping, and because Trofile has certain limits: It requires a high-volume blood sample and it cannot be used on samples from people with a viral load under 1000 copies. Genotypic methods analyze mutations in the V3 region of HIV-1's env gene to predict coreceptor use.
The Berlin maraviroc cohort included 92 patients at the time of this report [1]. There are only two inclusion criteria for this cohort: (1) beginning a maraviroc regimen after (2) being screened for coreceptor use by any method. Martin Obermeier and colleagues analyzed 84 people who had genotypic coreceptor testing (including 41 who had genotyping but no Trofile phenotyping) and 49 people who had Trofile testing (including 40 with the original Trofile assay and 9 with the enhanced assay). The enhanced Trofile test does a better than the original assay in detecting viruses that make up small proportions of a person's viral population.
Most cohort member studied, 92%, had subtype B HIV-1. In 76% of samples analyzed by the two methods, both Trofile and geno2pheno determined that the virus used CCR5. In 10% of these samples, both tests indicated that virus used CXCR4. In 8% of samples, Trofile saw R5 virus and geno2pheno saw X4, and in 6% Trofile saw X4 while geno2pheno saw R5.
After taking a maraviroc-including salvage regimen for 12 weeks, 47 of 63 people (75%) had a viral load below 50 copies or at least a 3-log (1000-fold) drop in viral load. After 24 weeks of maraviroc, 44 of 59 people (still 75%) were virologic responders by these criteria.
Positive and negative predictive values of geno2pheno vary according to where the false-positive rate is set when running the test. With a false-positive setting of 10%, geno2pheno had a positive predictive value for virologic response essentially equivalent to that of Trofile at around 75%. The negative predictive value of both tests was only 50%, but that result is hard to interpret because only 6 people had CXCR4-using virus by either geno2pheno or Trofile. Obermeier also cautioned that use of the integrase inhibitor raltegravir by more than half of the cohort probably affected virologic outcomes and represents a bias in the Berlin study group
A 106-patient study at London's Royal Free Hospital and University College Medical School found good correlation between the enhanced Trofile assay and geno2pheno predictions based on V3 sequences and clinical data [2]. Fifty-six of these people (53%) had no antiretroviral experience when screened for coreceptor use. This study focused on the geno2pheno clinical model, which requires input of CD4 count and percent, CD8 count, and viral load.
Trofile successfully determined coreceptor use in 93 of these people (88%), rating 80 samples R5 and 13 dual-mixed (meaning that person's HIV population can use either CCR5 or CXCR4). Angela Strang and colleagues successfully amplified 99 samples (93%) for geno2pheno analysis.
In 87 samples with enhanced Trofile and geno2pheno coreceptor calls, results agreed in 79 samples (91%) when geno2pheno had a false-positive setting of 10% and in 78 (90%) at a false-positive setting of 15%. Compared with enhanced Trofile results, geno2pheno with a false-positive setting of 10% had 96% specificity in determining CXCR4 use but a sensitivity of only 69%.
Strang and coworkers proposed that "geno2pheno provides a valid tropism prediction tool," while Obermeier and colleagues concluded that "genotypic tropism testing with geno2pheno has a comparable predictive value for therapeutic success as the Trofile assay and can be used in a clinical routine setting."
Charles Boucher from Erasmus University in Rotterdam, a long-time supporter of genotyping in clinical practice, maintained that both conclusions overstated study results. He argued that sensitivity of 70% to 80% is not good enough to support a blanket recommendation for genotyping to determine coreceptor use.
Anna Maria Geretti from London's Royal Free Hospital, who was senior investigator on Strang's study [2], agreed that these are early data. But she insisted that clinical investigators should strenuously pursue genotyping as a tool to call receptor use because so many patients can profit from the drug, if their coreceptor use is correctly determined.
Jonathan Schapiro from Sheba Medical Center in Israel noted that HIV clinicians have plenty of experience using tools that lack clinical validation. But he cautioned that data sets on genotyping for coreceptor determinations remain small.
References
1. Obermeier M, Carganico A, Berg T, et al. The Berlin maraviroc cohort: influence of genotypic tropism testing results on therapeutic outcome. 7th European HIV Drug Resistance Workshop, March 25-27, 2009, Stockholm. Abstract 79.
2. Strang A, Cameron J, Booth C, Garcia Diaz A, Geretti A. Genotypic prediction of viral co-receptor tropism: correlation with enhanced Trofile. 7th European HIV Drug Resistance Workshop, March 25-27, 2009, Stockholm. Abstract 80.
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