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The Body PRO Covers: The 40th Annual Meeting of the Infectious Diseases Society of America

Phenotyping and Therapeutic Drug Monitoring Complement Genotyping in Optimizing Therapy for HIV Patients

October 26, 2002

  • Phenotyping and Therapeutic Drug Monitoring Complement Genotyping in Optimizing Therapy for HIV Patients (Poster 458)
    Authored by Cynthia J. Carlyn, Aldona L. Baltch, Stratton VA Medical Ctr. & Albany Medical Coll., Albany, NY; Marty St. Clair, GlaxoSmithKline, Durham, NC; Richard A. Grembocki, Stratton VA Medical Ctr., Albany, NY; Mary J. George, Stratton VA Medical Ctr. & Albany Medical Coll., Albany, NY; Michael Bates, Nicholas Hellmann, ViroLogic Inc., S. San Francisco, CA; Gene Morse, Univ. at Buffalo, Buffalo, NY; Mark I. Becker, Agouron Pharmaceuticals, Inc., a Pfizer Company, La Jolla, DE; Raymond P. Smith, Stratton VA Medical Ctr. & Albany Medical Coll., Albany, NY


Questions remain unanswered regarding the best laboratory methods to assist providers and patients in choosing optimal antiretroviral therapy (ART). Previous studies have demonstrated improved patient outcomes when providers choose antiretroviral therapy regimens with guidance from genotype and phenotype results. It is less clear what the clinical utility of therapeutic drug monitoring (TDM) and replicative capacity (RC) is. Some experts have suggested that therapeutic drug monitoring may be useful in monitoring for toxicity (e.g., nephrolithiasis is associated with high levels of indinavir [IDV, Crixivan]). Others have suggested that it may be useful for patients who have not yet obtained an undetectable viral load due to inadequate levels of a protease inhibitor such as nelfinavir (NFV, Viracept). Definitive studies evaluating the clinical utility of therapeutic drug monitoring are still in progress and this has not become standard practice in the U.S.A.

Replicative capacity has been purported to be a surrogate marker for viral fitness. It would be difficult to measure the actual replicative capacity as it is dependent on an individual's immune response and exposure to antiretovirals, which cannot be mimicked in a laboratory test. Nevertheless, some providers have been using the replicative capacity assay results in order to continue an antiretroviral regimen that is "failing" in the setting of an unfit virus. Further studies are warranted exploring the clinical utility of replicative capacity.

Dr. Carlyn and colleagues conducted a pilot study to evaluate the clinical effectiveness of these assays. Twenty HIV-1 infected patients were clinically managed by expert advice and interpretation of results from genotyping (GT), phenotyping (PT), viral replicative capacity (replicative capacity) and therapeutic drug monitoring (therapeutic drug monitoring). Thirteen patients previously taking antiretroviral therapy selected by genotyping, had baseline viral loads (VL) of less than 50 to 10,880 copies/ml, and were followed for 68-110 weeks. Seven new patients (baseline viral load less than 50-64,804) were also enrolled. Genotyping was performed in 14 patients (viral load greater than 50) and phenotyping in eight patients (viral load greater than 500). Genotyping revealed primary viral mutations to nucleoside reverse transcriptase inhibitors (NRTI) in 11/14, to non-nucleoside reverse transcriptase inhibitors (NNRTI) in 9/14, and to protease inhibitors (PI) in 5/14.

Phenotyping detected decreased susceptibilities to at least 1 NRTI in five out of eight patients, to at least 1 NNRTI in four out of eight patients, and to one PI in two out of eight patients. Genotyping and phenotyping were discrepant in two of eight patients. In one patient the phenotype showed class nucleoside resistance, and in the other decreased susceptibility to ddI (didanosine, Videx) and ddC (zalcitabine, Hivid) (not detected by genotyping). Phenotyping indicated that the T215S mutation had little effect on d4T (stavudine, Zerit) or AZT (zidovudine, Retrovir) resistance.

Antiretroviral therapy was changed depending on genotyping and phenotyping data, but not drug levels. Therapies were changed in seven patients (six attained viral loads less than 50), and were not changed in 13 patients, either because they were already taking optimal regimens or because their viral loads were less than 50. Using therapeutic drug monitoring, three groups were identified: good responders with low drug levels, good responders with therapeutic or high levels, and poor responders with low levels. Generally, high drug levels were associated with patients who had hepatitis C co-infection, and low levels with non-adherence. Replicative capacity of patient virus was low (6-45 percent, median 12 percent) in this cohort.

At 36 weeks, 18 patients were doing well (12 had a viral load less than 50). Of the 13 patients whose therapies were selected by genotyping prior to this study, 12 continued to do well at 104-146 weeks. As the authors concluded, phenotyping complemented the results of genotyping and may be clinically useful in cases in which multiple mutations existed or in the setting where a mutation may be associated with resistance but not always. They did not change antiretroviral therapy based upon therapeutic drug monitoring and, as has been noted previously, some of their patients continued to have good virologic response despite having suboptimal drug levels. No interpretation can be made about the clinical utility of replicative capacity in this cohort. Larger, randomized trials evaluating the clinical utility of these assays are needed.


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This article was provided by TheBodyPRO.com. It is a part of the publication 40th Annual Meeting of the Infectious Diseases Society of America.
 



Please note: Knowledge about HIV changes rapidly. Note the date of this summary's publication, and before treating patients or employing any therapies described in these materials, verify all information independently. If you are a patient, please consult a doctor or other medical professional before acting on any of the information presented in this summary. For a complete listing of our most recent conference coverage, click here.
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